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CLAIMS 1. A compound of Formula ID: or a pharmaceutically acceptable salt or solvate thereof, wherein: A is selected from the group consisting of -N(R1a)- and -C(R')-OC(=O)(R8a)-; R1a is -L1-R1; L1 is C2-C6 alkylenyl or –(CH2)2-6-OC(=O)-; R1 is selected from the group consisting of -OH, R2a, R2b, and R2c are independently selected from the group consisting of hydrogen and C1-C6 alkyl; R3a, R3b, and R3c are independently selected from the group consisting of hydrogen and C1-C6 alkyl; R4a, R4b, and R4c are independently selected from the group consisting of hydrogen and C1-C6 alkyl; R5a, R5b, and R5c are independently selected from the group consisting of hydrogen and C1-C6 alkyl; R6a, R6b, and R6c are independently selected from the group consisting of hydrogen and C1-C6 alkyl; or R6a and R6b taken together with the nitrogen atom to which they are attached form a 4-to 8-membered heterocyclo; and R6c is selected from the group consisting of hydrogen and C1-C6 alkyl; R7a, R7b, and R7c are independently selected from the group consisting of hydrogen and C1-C6 alkyl; or R7a and R7b taken together with the nitrogen atom to which they are attached form a 4-to 8-membered heterocyclo; and R7c is selected from the group consisting of hydrogen and C1-C6 alkyl; R' is selected from the group consisting of hydrogen and C1-C6 alkyl; R8a is - L2-R8; L2 is C2-C6 alkylenyl; R8 is selected from the group consisting of -NR9aR9b, R9a and R9b are independently selected from the group consisting of hydrogen and C1-C6 alkyl; or R9a and R9b taken together with the nitrogen atom to which they are attached form a 4-to 8-membered heterocyclo; Q1 is C1-C20 alkylenyl; W1 is selected from the group consisting of -C(=O)O-, -OC(=O)-, -C(=O)N(R12a)- , -N(R12a)C(=O)-, -OC(=O)N(R12a)-, - N(R12a)C(=O)O-, and -OC(=O)O-; R12a is selected from the group consisting of hydrogen and C1-C6 alkyl; X1 is optionally substituted branched C1-C15 alkylenyl; or X1 is a bond; Y1 is selected from the group consisting of -(CH2)m-, -O-, -S-, and -S-S-; m is 0, 1, 2, 3, 4, 5, or 6; Z1 is optionally substituted C5-C12 bridged cycloalkylenyl; R10 is selected from the group consisting of hydrogen, C1-C20 alkyl, and C2-C20 alkenyl; Q2 is C1-C20 alkylenyl; W2 is selected from the group consisting of -C(=O)O-, -C(=O)N(R12b)-, -OC(=O)N(R12b)- , and -OC(=O)O-; R12b is selected from the group consisting of hydrogen and C1-C6 alkyl; X2 is optionally substituted C1-C15 alkylenyl; or Y2 is -(CH2)n-; n is 0, 1, 2, 3, 4, 5, or 6; Z2 is of -(CH2)p-; p is 0 or 1; and R11 is C1-C20 branched alkyl. 2. The compound of claim 1 of Formula II: or a pharmaceutically acceptable salt or solvate thereof. 3. The compound of claim 1 of Formula III: or a pharmaceutically acceptable salt or solvate thereof. 4. The compound of any of claims 1-3, wherein W1 is -C(=O)O- or -OC(=O)-. 5. The compound of any of claims 1-4, wherein W2 is -C(=O)O- or -OC(=O)-. 6. The compound of claim 1 of Formula VI, VI’, VI’’, or VI’’’: or a pharmaceutically acceptable salt or solvate thereof. 7. The compound of claim 1 of Formula VII, VII’, VII’’, or VII’’’: or a pharmaceutically acceptable salt or solvate thereof. 8. The compound of any of claims 1-7, wherein Q1 is optionally substituted straight chain C1-C10 alkylenyl, and Q2 is optionally substituted straight chain C1-C10 alkylenyl. 9. The compound of claim 8, wherein Q1 is optionally substituted straight chain C3-C7 alkylenyl, and Q2 is optionally substituted straight chain C3-C7 alkylenyl. 10. The compound of claim 9, wherein Q1 is selected from the group consisting of -CH2CH2CH2-, -CH2(CH2)2CH2-, -CH2(CH2)3CH2-, -CH2(CH2)4CH2-, and -CH2(CH2)5CH2-, and Q2 is selected from the group consisting of -CH2CH2CH2- , -CH2(CH2)2CH2-, -CH2(CH2)3CH2-, -CH2(CH2)4CH2-, and -CH2(CH2)5CH2-. 11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is a bond. 12. The compound of any of claims 1-11, wherein X2 is optionally substituted C1-C15 branched alkylenyl. 13. The compound of any of claims 1-3, -Q1-W1-X1-Y1-Z1-R10 is selected from the group consisting of: 14. The compound of any of claims 1-3, -Q2-W2-X2-Y2-Z2-R11 is selected from the group consisting of: 15. The compound of claim 1 of Formula XII’’: or a pharmaceutically acceptable salt or solvate thereof, wherein q1 is 0, 1, 2, or 3; q2 is 0, 1, 2, or 3; r2 is 0, 1, or 2; s2 is 0, 1, 2, 3, 4, 5, 6. 16. The compound of claim 1, of Formula XIII’ or a pharmaceutically acceptable salt or solvate thereof, wherein q1 is 0, 1, 2, or 3; q2 is 0, 1, 2, or 3; r2 is 0, 1, or 2; s2 is 0, 1, 2, 3, 4, 5, 6. 17. The compound of any of claims 1-16, wherein Z1 is optionally substituted C5-C12 bridged cycloalkylenyl. 18. The compound of claim 17, wherien Z1 is a optionally substituted C5-C10 bridged cycloalkylenyl. selected from the group consisting of adamantyl, cubanyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[1.1.1]pentyl, bicyclo[3.2.1]octyl, and bicyclo[3.1.1]heptyl. 19. The compound of claim 17, or a pharmaceutically acceptable salt or solvate thereof, wherein Z1 is selected from the group consisting of: 20. The compound of claim 19, or a pharmaceutically acceptable salt or solvate thereof, wherein Z1 is selected from the group consisting of: 21. The compound of any of claims 1-20, wherein Z2 is optionally substituted C5-C12 bridged cycloalkylenyl. 22. The compound of claim 21, wherien Z2 is a optionally substituted C5-C10 bridged cycloalkylenyl. selected from the group consisting of adamantyl, cubanyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[1.1.1]pentyl, bicyclo[3.2.1]octyl, and bicyclo[3.1.1]heptyl. 23. The compound of claim 22, or a pharmaceutically acceptable salt or solvate thereof, wherein Z2 is selected from the group consisting of: 24. The compound of claim 23, or a pharmaceutically acceptable salt or solvate thereof, wherein Z2 is selected from the group consisting of: 25. The compound of any of claims 1-20, wherein Z2 is -CH2-. 26. The compound of any of claims 1-25 of Formula XVII: or a pharmaceutically acceptable salt or solvate thereof, wherein q1 is 0, 1, 2, or 3; q2 is 0, 1, 2, or 3. 27. The compound of any of claims 1-25 of Formula XVIII: or a pharmaceutically acceptable salt or solvate thereof, wherein q1 is 0, 1, 2, or 3; q2 is 0, 1, 2, or 3. 28. The compound of any of claims 1-25 of Formula XIX: or a pharmaceutically acceptable salt or solvate thereof, wherein q1 is 0, 1, 2, or 3; q2 is 0, 1, 2, or 3. 29. The compound of any of claims 1-25 of Formula XXI: or a pharmaceutically acceptable salt or solvate thereof, wherein q1 is 0, 1, 2, or 3; q2 is 0, 1, 2, or 3. 30. The compound of any of claims 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is selected from the group consisting of -CH2CH2-, -CH2CH2CH2- , and -CH2CH2CH2CH2-. 31. The compound of claim 30, wherein L is -CH2CH2-. 32. The compound of claim 30, wherein L is -CH2CH2CH2-. 33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt or solvate thereof, wherein R9a and R9b are independently selected from the group consisting of hydrogen and C1-C4 alkyl. 34. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, wherein R9a and R9b are methyl. 35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt or solvate thereof, wherein R' is hydrogen. 36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is -(CH2)m-; and m is 1. 37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt or solvate thereof, wherein R10 is hydrogen. 38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt or solvate thereof, wherein Y2 is selected from the group consisting of -(CH2)m- and -S-. 39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt or solvate thereof, wherein R11 is C1-C10 alkyl. 40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt or solvate thereof, wherein R11 is C2-C10 alkenyl. 41. A compound selected from any one of more of the compounds of Table 1, or a pharmaceutically acceptable salt or solvate thereof. 42. A pharmaceutical composition comprising: (a) a polynucleotide encoding at least one protein of interest; and (b) a delivery vehicle comprising one or more compounds of any one of claims 1-41. 43. The pharmaceutical composition of claim 42, wherein the polynucleotides are DNA. 44. The pharmaceutical composition of claim 42, wherein the polynucleotides are RNA. 45. The pharmaceutical composition of claim 44, wherein the RNA are short interfering RNA (siRNA). 46. The pharmaceutical composition of claim 45, wherein the siRNA inhibits or suppresses the expression of a target of interest in a cell. 47. The pharmaceutical composition of any one of claims 43-46, wherein the polynucleotide comprises at least one modification. 48. The pharmaceutical composition of any of claims 42-47, further comprising an additional cationic lipid. 49. The pharmaceutical composition of any of claims 42-48, further comprising a neutral lipid. 50. The pharmaceutical composition of any of claims 42-49, further comprising an anionic lipid. 51. The pharmaceutical composition of any of claims 42-50, further comprising a helper lipid. 52. The pharmaceutical composition of any of claims 42-51, further comprising a stealth lipid. 53. The pharmaceutical composition of any of claims 42-52, wherein the weight ratio of the lipids and the polynucleotide is from about 100:1 to about 1:1. 54. A vaccine formulation comprising the pharmaceutical composition of any of claims 42-53. 55. A vaccine preparation comprising the pharmaceutical composition of any of claims 42-54. 56. A method of vaccinating a subject against an infectious agent comprising: a) contacting a subject with the vaccine formulation of claim 54 or the vaccine preparation of claim 55, and b) eliciting an immune response. 57. A method of delivering a polynucleotide encoding at least one protein of interest to an immune cell of a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any one of claims 42-53. 58. The method of claim 57, wherein the immune cell is a T cell. 59. The method of claim 58, wherein the T cell is a CD8+ T cell. 60. The method of claim 59, wherein the T cell is a T regulatory cell. 61. The method of claim 60, wherein the T cell is a CD4+ T cell. 62. The method of claim 61, wherein the immune cell is a macrophage, dendritic cell, or liver immune cell. 63. A lipid nanoparticle (LNP) comprising a compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof. 64. The LNP of claim 63, further comprising: (a) a PEG-lipid (b) a structural lipid; and (c) a non-ionizable lipid and/or a zwitterionic lipid. 65. The LNP of claim 64, wherein the ionizable lipid comprises an ionizable amino lipid. 66. The LNP of claim 64 or 65, wherein the PEG-lipid is selected from the group consisting of PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG-DMPE, PEG-DPPC, and PEG-DSPE. 67. The LNP of any one of claims 64-66, wherein the structural lipid is selected from the group consisting of cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, an alpha-tocopherol. 68. The LNP of any one of claims 64-67, wherein the non-ionizable lipid is a phospholipid selected from the group consisting of 1,2-distearoyl-sn-glycero-3- phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero- phosphocholine (DMPC), 1.2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2- dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-diundecanoyl-sn-glycero- phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocho line (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1- oleoyl-2-cholesterylhemisuc cinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1- hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero- 3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2- didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-diphytanoylsn-glycero-3- phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3- phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2- dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3- phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), sodium (S)- 2-ammonio-3-((((R)-2-(oleoyloxy)-3- (stearoyloxy)propoxy)oxidophosphoryl)oxy)propanoate (L-α-phosphatidylserine; Brain PS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dioleoyl- phosphatidylethanolamine4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dioleoylphosphatidylglycerol (DOPG), 1,2-dioleoyl-sn-glycero-3- (phospho-L-serine) (DOPS), acell-fusogenicphospholipid (DPhPE), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylcholine (DSPC), distearoyl-phosphatidyl-ethanolamine (DSPE), distearoyl phosphoethanolamineimidazole (DSPEI), 1,2-diundecanoyl-sn-glycero- phosphocholine (DUPC), egg phosphatidylcholine (EPC), 1,2-dioleoyl-sn-glycero-3- phosphate (18:1 PA; DOPA), ammonium bis((S)-2-hydroxy-3-(oleoyloxy)propyl) phosphate (18:1 DMP; LBPA), 1,2-dioleoyl-sn-glycero-3-phospho-(1’-myo-inositol) (DOPI; 18:1 PI), 1,2-distearoyl-sn-glycero-3-phospho-L-serine (18:0 PS), 1,2- dilinoleoyl-sn-glycero-3-phospho-L-serine (18:2 PS), 1-palmitoyl-2-oleoyl-sn- glycero-3-phospho-L-serine (16:0-18:1 PS; POPS), 1-stearoyl-2-oleoyl-sn-glycero-3- phospho-L-serine (18:0-18:1 PS), 1-stearoyl-2-linoleoyl-sn-glycero-3-phospho-L- serine (18:0-18:2 PS), 1-oleoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:1 Lyso PS), 1-stearoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:0 Lyso PS), and sphingomyelin. 69. The LNP of any one of claims 64-68, further comprising a targeting moiety. 70. The LNP of claim 69, wherein the targeting moiety is an antibody or a fragment thereof. 71. The LNP of any one of claims 64-70, further comprising an active agent. 72. The LNP of claim 71, wherein the active agent is a nucleic acid. 73. The LNP of claim 72, wherein the nucleic acid is a ribonucleic acid. 74. The LNP of claim 73, wherein the ribonucleic acid is at least one ribonucleic acid selected from the group consisting of a small interfering RNA (siRNA), an asymmetrical interfering RNA (aiRNA), a microRNA (miRNA), a Dicer-substrate RNA (dsRNA), a small hairpin RNA (shRNA), a messenger RNA (mRNA), and a long non-coding RNA (lncRNA). 75. The LNP of claim 72, wherein the nucleic acid is a messenger RNA (mRNA) or a circular RNA. 76. The LNP of claim 75, wherein the mRNA includes an open reading frame encoding a cancer antigen. 77. The LNP of claim 76, wherein the mRNA includes an open reading frame encoding an immune checkpoint modulator. 78. The LNP of any one of claims 75-77, wherein the mRNA includes at least one motif selected from the group consisting of a stem loop, a chain terminating nucleoside, a polyA sequence, a polyadenylation signal, and a 5' cap structure. 79. The LNP of claim 72, wherein, wherein the nucleic acid is a polynucleotide that encodes a protein selected from SEQ ID NOs: 1-54. 80. The LNP of claim 72, wherein the nucleic acid is suitable for a genome editing technique. 81. The LNP of claim 80, wherein the genome editing technique is clustered regularly interspaced short palindromic repeats (CRISPR) or transcription activator-like effector nuclease (TALEN). 82. The LNP of claim 72, wherein the nucleic acid is at least one nucleic acid suitable for a genome editing technique selected from the group consisting of a CRISPR RNA (crRNA), a trans-activating crRNA (tracrRNA), a single guide RNA (sgRNA), and a DNA repair template. 83. The LNP of claim 75, wherein the mRNA is at least 30 nucleotides in length. 84. The LNP of claim 75, wherein the mRNA is at least 300 nucleotides in length. 85. A pharmaceutical composition comprising a LNP of any one of claims 63-84, and a pharmaceutically acceptable carrier. 86. The pharmaceutical composition of claim 85, formulated for intravenous or intramuscular administration. 87. The pharmaceutical composition of claim 86, which is formulated for intravenous administration. 88. A method for delivering a nucleic acid to a cell comprising contacting the cell with a LNP of any one of claims 63-84 or a pharmaceutical composition of any one of claims 85-87. 89. A method for treating a disease characterized by a deficieincy of a functional protein, the method comprising administering to a subject having the disease, a LNP formulation comprising a LNP of any one of claims 63-84, wherein the mRNA encodes the functional protein or a protein having the same biological activity as the functional protein. 90. A method for treating a disease characterized by overexpression of a polypeptide, comprising administering to a subject having the disease a LNP formulation comprising a LNP of any one of claims 63-84 and a siRNA, wherein the siRNA targets expression of the overexpressed polypeptide 91. A method of delivering a polynucleotide encoding at least one protein of interest to a cell of interest of a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any one of claims 42-53, 85-87 or a LNP of any one of claims 63-84. 92. The mehod of claim 91, wherein the cell is selected from the group consisting of hepatocyte, epithelial cell, hematopoietic cell, epithelial cell, endothelial cell, lung cell, bone cell, stem cell, mesenchymal cell, neural cell, cardiac cell, adipocyte, vascular smooth muscle cell, cardiomyocyte, skeletal muscle cell, beta cell, pituitary cell, synovial lining cell, ovarian cell, testicular cell, fibroblast, B cell, T cell, reticulocyte, leukocyte, granulocyte, and tumor cell. 93. The method of claim 91, wherein the cell is an immune cell. 94. The method of claim 93, wherein the immune cell is a T cell. 95. The method of claim 94, wherein the T cell is a CD8+ T cell. 96. The method of claim 94, wherein the T cell is a T regulatory cell. 97. The method of claim 94, wherein the T cell is CD4+ T cell. 98. The method of claim 93, wherein the immune cell is a B cell. 99. The method of claim 94, wherein the immune cell is a macrophage, dendritic cell, or liver immune cell. 100. The method of claim 91, wherein the cell is a hematopoietic cell. |
[0630] In some embodiments, Q 2 -W 2 -X 2 -Y 2 -Z 2 -R 11 is selected from the group consisting of:
[0631] In some embodiments, -W 1 -X 1 -Y 1 -Z 1 -R 10 is selected from the group consisting of:
[0632] In some embodiments, -W 2 -X 2 -Y 2 -Z 2 -R 11 is selected from the group consisting of:
[0633] In another embodiment, the disclosure provides a compound selected from any one of more of the compounds of Table 1, or a pharmaceutically acceptable salt or solvate thereof. Table 1 IV. DELIVERY VEHICLES AND TRACKING SYSTEMS [0634] Originator constructs and benchmark constructs described herein may be formulated in a delivery vehicle. Non-limiting examples of delivery vehicles include lipid nanoparticles, non- lipid nanoparticles, exosomes, liposomes, micelles, viral particles, and polymeric delivery technology. [0635] In some embodiments, the delivery vehicle comprises at least one lipid in Table (I). [0636] In some embodiments, the delivery vehicle comprises at least two lipids in Table (I). [0637] In some embodiments, the delivery vehicle comprises at least three lipids in Table (I). [0638] In some embodiments, the delivery vehicle comprises at least four lipids in Table (I). [0639] The total weight percentage of the lipid(s) in Table (I) in the delivery vehicle is between about 10% to about 95%, such as between about 10% to about 20%, between about 21% to about 30%, between about 31% to about 40%, between about 41% to about 50%, between about 51% to about 60%, between about 61% to about 70%, between about 71% to about 80%, between about 81% to about 90%, or between about 91% to about 95%. [0640] The total mole percentage of the lipid(s) in Table (I) in the delivery vehicle is between about 10% to about 95%, such as between about 10% to about 20%, between about 21% to about 30%, between about 31% to about 40%, between about 41% to about 50%, between about 51% to about 60%, between about 61% to about 70%, between about 71% to about 80%, between about 81% to about 90%, or between about 91% to about 95%. [0641] In some embodiments, at least one lipid in the delivery vehicle has a structure of any of Formulae I-VII. [0642] In some embodiments, at least two lipids in the delivery vehicle have a structure of any of Formulae I-VII. [0643] In some embodiments, at least three lipids in the delivery vehicle have a structure of any of Formulae I-VII. [0644] In some embodiments, at least four lipids in the delivery vehicle have a structure of any of Formulae I-VII. [0645] The total weight percentage of the lipid(s) having a structure of any of Formulae I-VII in the delivery vehicle is between 10%-95%, such as between about 10% to about 20%, between about 21% to about 30%, between about 31% to about 40%, between about 41% to about 50%, between about 51% to about 60%, between about 61% to about 70%, between about 71% to about 80%, between about 81% to about 90%, or between about 91% to about 95%. [0646] The total mole percentage of the lipid(s) having a structure of any of Formulae I-VII in the delivery vehicle is between 10%-95%, such as between about 10% to about 20%, between about 21% to about 30%, between about 31% to about 40%, between about 41% to about 50%, between about 51% to about 60%, between about 61% to about 70%, between about 71% to about 80%, between about 81% to about 90%, or between about 91% to about 95%. [0647] In some embodiments, the delivery vehicle further comprises at lease one additional lipid. Non-limiting examples include an additional cationic lipid, a neutral lipid, an anionic lipid, a helper lipid, a stealth lipid, or a polyethylene glycol (PEG) lipid. [0648] "Helper lipids" are lipids that enhance transfection, such as transfection of the delivery vehicle including the payloads and cargos. The mechanism by which the helper lipid enhances transfection may include enhancing particle stability and/or enhancing membrane fusogenicity. Helper lipids include steroids and alkyl resorcinols. Helper lipids suitable for use in the present disclosure include, but are not limited to, cholesterol, 5-heptadecylresorcinol, and cholesterol hemisuccinate. [0649] "Stealth lipids" are lipids that extend the length of time for which the delivery vehicle can exist in vivo (e.g. in the blood). Stealth lipids suitable for use in a lipid composition of the present disclosure include, but are not limited to, stealth lipids having a hydrophilic head group linked to a lipid moiety. [0650] Non-limiting examples of cationic lipids suitable for use in the delivery vehicle of the present disclosure include, but are not limited to, N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), N,N-distearyl-N,N-dimethylammonium bromide (DDAB), N-(1-(2,3- dioleoyloxy) propyl)-N,N,N-trimethylammonium chloride (DOTAP), 1,2-Dioleoyl-3- Dimethylammonium-propane (DODAP), N-(1-(2,3-dioleyloxy)propyl)-N,N,N- trimethylammonium chloride (DOTMA), 1,2-Dioleoylcarbamyl-3-Dimethylammonium- propane (DOCDAP), 1,2-Dilineoyl-3-Dimethylammonium-propane (DLINDAP), dilauryl(C12:0) trimethyl ammonium propane (DLTAP), Dioctadecylamidoglycyl spermine (DOGS), DC-Choi, Dioleoyloxy-N-[2-sperminecarboxamido)ethyl}-N,N-dimethyl-1- propanaminiumtrifluoroacetate (DOSPA), 1,2-Dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide (DMRIE), 3-Dimethylamino-2-(Cholest-5-en-3-beta-oxybutan-4-oxy)-1- (cis,cis-9,12-octadecadienoxy)propane (CLinDMA), N,N-dimethyl-2,3- dioleyloxy)propylamine (DODMA), 2-[5′-(cholest-5-en-3[beta]-oxy)-3′-oxapentoxy)-3- dimethyl-1-(cis,cis-9′,12′-octadecadienoxy) propane (CpLinDMA) and N,N-Dimethyl-3,4- dioleyloxybenzylamine (DMOBA), and 1,2-N,N′-Dioleylcarbamyl-3-dimethylaminopropane (DOcarbDAP). [0651] Non-limiting example of neutral lipids suitable for use in the delivery vehicle of the present disclosure include a variety of neutral, uncharged or zwitterionic lipids. Examples of neutral phospholipids suitable for use in the present disclosure include, but are not limited to: 5-heptadecylbenzene-1,3-diol (resorcinol), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), phosphocholine (DOPC), dimyristoylphosphatidylcholine (DMPC), phosphatidylcholine (PLPC), 1,2-distearoyl-sn- glycero-3-phosphocholine (DAPC), phosphatidylethanolamine (PE), egg phosphatidylcholine (EPC), dilauryloylphosphatidylcholine (DLPC), dimyristoylphosphatidylcholine (DMPC), 1- myristoyl-2-palmitoyl phosphatidylcholine (MPPC), 1-palmitoyl-2-myristoyl phosphatidylcholine (PMPC), 1-palmitoyl-2-stearoyl phosphatidylcholine (PSPC), 1,2- diarachidoyl-sn-glycero-3-phosphocholine (DBPC), 1-stearoyl-2-palmitoyl phosphatidylcholine (SPPC), 1,2-dieicosenoyl-sn-glycero-3-phosphocholine (DEPC), palmitoyloleoyl phosphatidylcholine (POPC), lysophosphatidyl choline, dioleoyl phosphatidylethanolamine (DOPE), dilinoleoylphosphatidylcholine distearoylphophatidylethanolamine (DSPE), dimyristoyl phosphatidylethanolamine (DMPE), dipalmitoyl phosphatidylethanolamine (DPPE), palmitoyloleoyl phosphatidylethanolamine (POPE), lysophosphatidylethanolamine and combinations thereof. [0652] Non-limiting examples of anionic lipids suitable for use in the delivery vehicle of the present disclosure include, but are not limited to, phosphatidylglycerol, cardiolipin, diacylphosphatidylserine, diacylphosphatidic acid, N-dodecanoyl phosphatidyl ethanoloamine, N-succinyl phosphatidylethanolamine, N-glutaryl phosphatidylethanolamine cholesterol hemisuccinate (CHEMS), and lysylphosphatidylglycerol. [0653] In some embodiments, the weight ratio of the delivery vehicle (including all the lipids) and the payload is between about 100:1 to about 1:1, such as between about 100:1 to about 90:1, between about 89:1 to about 80:1, between about 79:1 to about 70:1, between about 69:1 to about 60:1, between about 59:1 to about 50:1, between about 49:1 to about 40:1, between about 39:1 to about 30:1, between about 29:1 to about 20:1, between about 19:1 to about 10:1, and between about 9:1 to about 1:1. [0654] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with at least one cargo or payload. The cargo or payload may be any DNA, RNA or polypeptide described herein. [0655] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with at least one cargo or payload which is a coding RNA. [0656] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with at least one cargo or payload which is a non-coding RNA. [0657] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with at least one cargo or payload which is a oRNA. [0658] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with at least one cargo or payload which is an mRNA. [0659] In some embodiments, the at least one RNA compound is comprised of a functional RNA where the RNA results in at least one change in a cell, tissue, organ and/or organism. Said changes in state may include, but are not limited to, altering the expression level of a polypeptide, altering the translation level of a nucleic acid, altering the expression level of a nucleic acid, altering the amount of a polypeptide present in a cell, tissue, organ and/or organism, changing a genetic sequence of a cell, tissue, organ and/or organism, adding nucleic acids to a target genome, subtracting nucleic acids from a target genome, altering physiological activity in a cell, tissue, organ and/or organism or any combination thereof. [0660] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with at least one cargo or payload which is DNA. [0661] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with two cargos or payloads which are DNA. The DNA may be the same DNA or different DNA. As a non-limiting example, the DNA are the same. As a non-limiting example, the DNA are different. As a non-limiting example, the DNA are different but encode the same payload or cargo. As a non-limiting example, the DNA are different pieces of a larger payload or cargo (e.g., heavy chain or light chain of an antibody) that can come together using natural systems or synthetic methods known in the art to produce a functional polypeptide (e.g., antibody). [0662] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with three cargos or payloads which are DNA. The DNA may be the same DNA or different DNA. As a non-limiting example, the DNA are the same. As a non-limiting example, the DNA are different. As a non-limiting example, two DNA are the same and one is different. As a non-limiting example, the first DNA is different from the second and third DNA. As a non-limiting example, the first DNA, second DNA and third DNA are all different. As a non-limiting example, the first DNA is different from the second and third DNA but they all encode the same payload or cargo. As a non-limiting example, the first DNA is different from the second and third DNA but the second and third DNA encode the same payload or cargo. [0663] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with at least one cargo or payload which is a polypeptide. [0664] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with two cargos or payloads which are polypeptide. The polypeptide may be the same polypeptide or different polypeptide As a non-limiting example, the polypeptide are the same. As a non-limiting example, the polypeptide are different. As a non-limiting example, the polypeptides are different pieces of a larger payload or cargo (e.g., heavy chain or light chain of an antibody) that can come together using natural systems or synthetic methods known in the art to produce a functional polypeptide (e.g., antibody). [0665] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with three cargos or payloads which are polypeptide. The polypeptide may be the same polypeptide or different polypeptide. As a non-limiting example, the polypeptide are the same. As a non-limiting example, the polypeptide are different. As a non- limiting example, two polypeptide are the same and one is different. As a non-limiting example, the first polypeptide is different from the second and third polypeptide. As a non-limiting example, the first polypeptide, second polypeptide and third polypeptide are all different. As a non-limiting example, the first polypeptide is different from the second and third polypeptide but they all encode the same payload or cargo. As a non-limiting example, the first polypeptide is different from the second and third polypeptide but the second and third polypeptide encode the same payload or cargo. [0666] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with at least one cargo or payload which is a peptide. [0667] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with two cargos or payloads which are peptide. The peptide may be the same peptide or different peptide. As a non-limiting example, the peptide are the same. As a non-limiting example, the peptides are different. As a non-limiting example, the peptides are different pieces of a larger payload or cargo (e.g., heavy chain or light chain of an antibody) that can come together using natural systems or synthetic methods known in the art to produce a functional polypeptide (e.g., antibody). [0668] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with three cargos or payloads which are peptide. The peptide may be the same peptide or different peptide. As a non-limiting example, the peptides are the same. As a non-limiting example, the peptides are different. As a non-limiting example, two peptides are the same and one is different. As a non-limiting example, the first peptide is different from the second and third peptide. As a non-limiting example, the first peptide, second peptide and third peptide are all different. As a non-limiting example, the first peptide is different from the second and third peptide but they all encode the same payload or cargo. As a non-limiting example, the first peptide is different from the second and third peptide but the second and third peptide encode the same payload or cargo. [0669] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with at least one cargo or payload which is RNA. [0670] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with two cargos or payloads which are RNA. The RNA may be the same RNA or different RNA. As a non-limiting example, the RNAs are the same. As a non-limiting example, the RNAs are different. As a non-limiting example, the RNAs are different but encode the same payload or cargo. As a non-limiting example, the RNAs are different pieces of a larger payload or cargo (e.g., heavy chain or light chain of an antibody) that can come together using natural systems or synthetic methods known in the art to produce a functional polypeptide (e.g., antibody). [0671] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with three cargos or payloads which are RNA. The RNA may be the same RNA or different RNA. As a non-limiting example, the RNA are the same. As a non-limiting example, the RNA are different. As a non-limiting example, two RNA are the same and one is different. As a non-limiting example, the first RNA is different from the second and third RNA. As a non-limiting example, the first RNA, second RNA and third RNA are all different. As a non-limiting example, the first RNA is different from the second and third RNA but they all encode the same payload or cargo. As a non-limiting example, the first RNA is different from the second and third RNA but the second and third RNA encode the same payload or cargo. [0672] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with two cargos or payloads where one is RNA and one is DNA. The RNA and DNA may encode the same peptide or polypeptide or may encode different peptides or polypeptides. As a non-limiting example, the RNA and DNA may encode the same peptide or polypeptide. As a non-limiting example, the RNA and DNA may encode different peptides or polypeptides. As a non-limiting example, the RNA and DNA are different pieces of a larger payload or cargo (e.g., heavy chain or light chain of an antibody) that can come together using natural systems or synthetic methods known in the art to produce a functional polypeptide (e.g., antibody). [0673] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with two cargos or payloads where one is RNA and one is a peptide. The RNA may encode the same peptide as the peptide cargo/payload the RNA may encode a different peptide. As a non-limiting example, the RNA encodes the same peptide. As a non- limiting example, the RNA encodes a different peptides. As a non-limiting example, the RNA and peptide are different pieces of a larger payload or cargo (e.g., heavy chain or light chain of an antibody) that can come together using natural systems or synthetic methods known in the art to produce a functional polypeptide (e.g., antibody). [0674] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with two cargos or payloads where one is RNA and one is a polypeptide. The RNA may encode the same polypeptide as the polypeptide cargo/payload the RNA may encode a different polypeptide. As a non-limiting example, the RNA encodes the same polypeptide. As a non-limiting example, the RNA encodes a different polypeptide. As a non- limiting example, the RNA and polypeptide are different pieces of a larger payload or cargo (e.g., heavy chain or light chain of an antibody) that can come together using natural systems or synthetic methods known in the art to produce a functional polypeptide (e.g., antibody). [0675] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with two cargos or payloads where one is DNA and one is a peptide. The DNA may encode the same peptide as the peptide cargo/payload the DNA may encode a different peptide. As a non-limiting example, the DNA encodes the same peptide. As a non- limiting example, the DNA encodes a different peptide. As a non-limiting example, the DNA and peptide are different pieces of a larger payload or cargo (e.g., heavy chain or light chain of an antibody) that can come together using natural systems or synthetic methods known in the art to produce a functional polypeptide (e.g., antibody). [0676] In some embodiments, the delivery vehicle comprises an originator construct or a benchmark construct with two cargos or payloads where one is DNA and one is a polypeptide. The DNA may encode the same polypeptide as the polypeptide cargo/payload the DNA may encode a different polypeptide. As a non-limiting example, the DNA encodes the same polypeptide. As a non-limiting example, the DNA encodes a different polypeptide. As a non- limiting example, the DNA and polypeptide are different pieces of a larger payload or cargo (e.g., heavy chain or light chain of an antibody) that can come together using natural systems or synthetic methods known in the art to produce a functional polypeptide (e.g., antibody). Delivery Vehicles Nanoparticles [0677] In some embodiments, the delivery vehicle is a nanoparticle. The term "nanoparticle" as used herein refers to any particle ranging in size from 10-1000 nm. The nanoparticle may be 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, or 1000 nm. Lipid Nanoparticles [0678] In some embodiments, the nanoparticles may be a lipid nanoparticle (LNP). In general, LNPs can be characterized as small solid or semi-solid particles possessing an exterior lipid layer with a hydrophilic exterior surface that is exposed to the non-LNP environment, an interior space which may aqueous (vesicle like) or non-aqueous (micelle like), and at least one hydrophobic inter-membrane space. LNP membranes may be lamellar or non-lamellar and may be comprised of 1, 2, 3, 4, 5 or more layers. In some embodiments, LNPs may comprise a cargo or a payload into their interior space, into the inter membrane space, onto their exterior surface, or any combination thereof. [0679] LNPs useful herein are known in the art and generally comprise cholesterol (aids in stability and promotes membrane fusion), a phospholipid (which provides structure to the LNP bilayer and also may aid in endosomal escape), a polyethylene glycol (PEG) derivative (which reduces LNP aggregation and "shields" the LNP from non-specific endocytosis by immune cells), and an ionizable lipid (complexes negatively charged RNA and enhances endosomal escape), which form the LNP-forming composition. [0680] The components of the LNP may be selected based on the desired target, cargo, size, etc. As a non-limiting example, previous studies have shown that that polymeric nanoparticles made of low molecular weight polyamines and lipids can deliver nucleic acids to endothelial cells with high efficiency. (Dahlman, et al., In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight, Nat Nanotechnol. 2014 Aug; 9(8): 648-655; the contents of which is herein incorporated by reference in its entirety). [0681] In some embodiments, the originator constructs and benchmark constructs of the present disclosure may be incorporated into lipid nanoparticles (LNPs). In some embodiments a lipid nanoparticle may be comprised of at least one cationic lipid, at least one non-cationic lipid, at least one sterol, at least one particle-activity-modifying-agent, or any combination thereof. In some embodiments a lipid nanoparticle may be comprised of at least one cationic lipid, at least one non-cationic lipid, at least one sterol, and at least one particle-activity- modifying-agent. In some embodiments, the LNP may be comprised of at least one cationic lipid, at least one non-cationic lipid, and at least one sterol. In some embodiments, the LNP may be comprised of at least one cationic lipid, at least one non-cationic lipid, and at least one particle-activity-modifying-agent. In some embodiments, the LNP may be comprised of at least one non-cationic lipid, at least one sterol, and at least one particle-activity-modifying-agent. In some embodiments, the LNP may be comprised of at least one cationic lipid and at least one non-cationic lipid. In some embodiments, the LNP may be comprised of at least one cationic lipid and at least one sterol. In some embodiments, the LNP may be comprised of at least one cationic lipid and at least one particle-activity-modifying-agent. In some embodiments, the LNP may be comprised of at least one non-cationic lipid and at least one sterol. In some embodiments, the LNP may be comprised of at least one non-cationic lipid and at least one particle-activity-modifying-agent. In some embodiments, the LNP may be comprised of at least one sterol and at least one particle-activity-modifying-agent. In some embodiments, the LNP may be comprised of at least one cationic lipid. In some embodiments, the LNP may be comprised of at least one non-cationic lipid. In some embodiments, a LNP may be comprised of a sterol. In some embodiments, the LNP may be comprised of a particle-activity-modifying- agent. [0682] In some embodiments, the at least one cationic lipid may comprise any of at least one ionizable cationic lipid, at least one amino lipid, at least one saturated cationic lipid, at least one unsaturated cationic lipid, at least one zwitterionic lipid, at least one multivalent cationic lipid, or any combination thereof. In some embodiments, the LNP may be essentially devoid of the at least one cationic lipid. In some embodiments, the LNP may contain no amount of the at least one cationic lipid. [0683] In some embodiments, at least one cationic lipid may be selected from, but not limited to, at least one of 1,3-Bis-(1,2-bis-tetradecyloxy-propyl-3- dimethylethoxyammoniumbromide)-propan-2-ol ((R)-PLC-2), 2-(Dinonylamino)ethan-1-ol (17-10), 2-(Didodecylamino)ethan-1-ol (17-11), 3-(Didodecylamino)propan-1-ol (17-12), 4- (Didodecylamino)butan-1-ol (17-13), 2-(Hexyl((9Z,12Z)-octadeca-9,12-dien-1- yl)amino)ethan-1-ol (17-2), 2-(Nonyl((9Z,12Z)-octadeca-9,12-dien-1-yl)amino)ethan-1-ol (17-3), 2-(Dodecyl((9Z,12Z)-octadeca-9,12-dien-1-yl)amino)ethan-1-ol (17-4), 2-(((9Z,12Z)- Octadeca-9,12-dien-1-yl)(tetradecyl)amino)ethan-1-ol (17-5), 2-(((9Z,12Z)-Octadeca-9,12- dien-1-yl)(octadecyl)amino)ethan-1-ol (17-6), 2-(Ditetradecylamino)ethan-1-ol (17-7), 2- (Di((Z)-octadec-9-en-1-yl)amino)ethan-1-ol (17-8), (9Z,12Z)-N-(2-Methoxyethyl)-N- ((9Z,12Z)-octadeca-9,12-dien-1-yl)octadeca-9,12-dien-1-amine (17-9), N-Nonyl-N-(2- (piperazin-1-yl)ethyl)nonan-1-amine (19-1), N-Dodecyl-N-(2-(piperazin-1-yl)ethyl)dodecan- 1-amine (19-2), (9Z,12Z)-N-((9Z,12Z)-Octadeca-9,12-dien-1-yl)-N-(2-(piperazi n-1- yl)ethyl)octadeca-9,12-dien-1-amine (19-3), N-Dodecyl-N-(2-(4-methylpiperazin-1- yl)ethyl)dodecan-1-amine1ntermediate1:2-(Didodecylamino)etha n-1-ol (19-4), N-Dodecyl- N-(2-(4-(4-methoxybenzyl)piperazin-1-yl)ethyl)dodecan-1-amin e (19-5), (9Z,12Z)-N-(2-(4- Dodecylpiperazin-1-yl)ethyl)-N-((9Z,12Z)-octadeca-9,12-dien- 1-yl)octadeca-9,12-dien-1- amine (19-6), (3-((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-ylox y)-N,N- dimethylpropan-1-amine) (1-Bl 1), N-(2-(Didodecylamino)ethyl)-N-dodecylglycine (20-1), Dinonyl8,8'-((2-(dodecyl(2-hydroxyethyl)amino)ethyl)azanediy l)dioctanoate (20-10), 3-((2- (Ditetradecylamino)ethyl)(dodecyl)amino)propan-1-ol (20-11), 2-((2- (Ditetradecylamino)ethyl)(tetradecyl)amino)ethan-1-ol (20-12), 2-((2-(Di((9Z,12Z)-octadeca- 9,12-dien-1-yl)amino)ethyl)(dodecyl)amino)ethan-1-ol (20-13), 2-((2-(Di((9Z,12Z)-octadeca- 9,12-dien-1-yl)amino)ethyl)((9Z,12Z)-octadeca-9,12-dien-1-yl )amino)ethan-1-ol (20-14), 2- ((2-(Didodecylamino)ethyl)(hexyl)amino)ethan-1-ol (20-15), 2-((2- (Dinonylamino)ethyl)(nonyl)amino)ethan-1-ol (20-16), 2-((2- (Didodecylamino)ethyl)(nonyl)amino)ethan-1-ol (20-17), 2-((2- (Dinonylamino)ethyl)(dodecyl)amino)ethan-1-ol (20-18), 2-((2- (Didodecylamino)ethyl)amino)ethan-1-ol (20-19), Pentyl6-(dodecyl(2-(dodecyl(2- hydroxyethyl)amino)ethyl)amino)hexanoate (20-2), 2-((2- (Didodecylamino)ethyl)(dodecyl)amino)ethan-1-ol (20-20), 3-((2- (Didodecylamino)ethyl)(dodecyl)amino)propan-1-ol (20-21), 4-((2- (Didodecylamino)ethyl)(dodecyl)amino)butan-1-ol (20-22), (Z)-2-((2- (Didodecylamino)ethyl)(dodec-6-en-1-yl)amino)ethan-1-ol (20-23), 2-((2- (Didodecylamino)ethyl)(tetradecyl)amino)ethan-1-ol (20-24), 2-((2- (Didodecylamino)ethyl)((9Z,12Z)-octadeca-9,12-dien-1-yl)amin o)ethan-1-ol (20-25), Pentyl6-((2-(didodecylamino)ethyl)(2-hydroxyethyl)amino)hexa noate (20-3), Dipentyl6,6'- ((2-(dodecyl(2-hydroxyethyl)amino)ethyl)azanediyl)dihexanoat e (20-4), Diheptyl6,6'-((2-((6- (heptyloxy)-6-oxohexyl)(2hydroxyethyl)amino)ethyl)azanediyl) dihexanoate (20-5), Pentyl6- ((2-(dinonylamino)ethyl)(2-hydroxyethyl)amino)hexanoate (20-6), Heptyl6-(dodecyl(2- (dodecyl(2-hydroxyethyl)amino)ethyl)amino)hexanoate (20-7), Nonyl8-((2- (didodecylamino)ethyl)(2-hydroxyethyl)amino)octanoate (20-8), Heptadecan-9-yl8-((2- (didodecylamino)ethyl)(2-hydroxyethyl)amino)octanoate (20-9), 1-(2,2-Di((9Z,12Z)- octadeca-9,12-dien-1-yl)cyclopropyl)-N,N-dimethylmethanamine (21-1), 3,3-Di((9Z,12Z)- octadeca-9,12-dien-1-yl)cyclobutyl4-(dimethylamino)butanoate (21-2), 3,3-Di((9Z,12Z)- octadeca-9,12-dien-1-yl)cyclopentyl3-(dimethylamino)propanoa te (21-3), 3,3-Di((9Z,12Z)- octadeca-9,12-dien-1-yl)cyclopentyl4-(dimethylamino)butanoat e (21-4), 1-(2,3-Di((8Z,11Z)- heptadeca-8,11-dien-1-yl)cyclopropyl)-N,N-dimethylmethanamin e (21-6), Unknown (75- 016B), poly{4-((2-(dimethylamino)ethyl)thio)tetrahydro-2H-pyran-2-o ne}-r-poly{4- (octylthio)tetrahydro-2H-pyran-2-one} (A7), (3aR5s,6aS)-N,N-dimethyl-2,2-di((9Z,12Z)- octadeca-9,12-dienyl)tetrahydro-3aH-cyclopentad1,3dioxol-5-a mine (ALN100), (3aR,5s,6aS)-N,N-dimethyl-2,2-di((9Z,12Z)-octadeca-9,12-dien yl)tetrahydro- 3aHcyclopenta[d][1,3]dioxol-5-amine (ALN1001), ((3aR,5s,6aS)-N,N-dimethyl-2,2- di((9Z,12Z)-octadeca-9,12-dienyl)tetrahydro-3aH-cyclopenta[d ][1,3]dioxol-5-amine)) (ALNY-100), dimyristoyltrimethylammoniumpropane (Amino Lipid 6), Benzamiπdiπ- dialkyl-carboxylicacid (BADACA), N,N-dihydroxyethylmethyl-N-2- (cholesteryloxycarbonylamino)ethylammoniumbromide (BHEM-Chol), N,N-bis-(2- hydroxyethyl)-N-methyl-N-(2-cholesteryloxycarbonylamino-ethy l)ammoniumbromide (BHEM-Chol1), 2-{4-[(3β)-cholest-5-en-3-yloxy]butoxy}-iV?N-dimethyl-3-[(9 Z,12Z)- octadeca-9!12-dien-1-yloxy]propan-1-amine (Butyl-CLinDMA), (2JR)-2-{4-[(3β)-cholest-5- en-3-yloxy]butoxy}-Λr^dimethyl-3-[(9Z,12Z)-octadeca-9!12-di en-1-yloxyjpropan-1-amine (Butyl-CLinDMA (2R)), (25)-2-{4-[(3β)-cholest-5-en-3-y1oxy]butoxy}-iVy/V-dimethyl -3- [(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-1-amine (Butyl-CLinDMA (2S)), 1,1'-(2-(4-(2- ((2-(bis(2-hydroxydodecyl)amino)ethyl)(2-hydroxydodecyl)amin o)ethyl)piperazin-1- yl)ethylazanediyl)didodecan-2-ol (C 12-200), 1,1'-((2-(4-(2-((2-(bis(2- hydroxydodecyl)amino)ethyl)(2-hydroxydodecyl)amino)ethyl)pip erazin-1- yl)ethyl)azanediyl)bis(dodecan-2-ol) (C12-200), Cholesteryl-succinyl Silane (C2), (9Z,9'Z,12Z,12'Z)-2-((4-(((3- (dimethylamino)propoxy)carbonyl)oxy)hexadecanoyl)oxy)propane -1,3-diylbis(octadeca- 9,12-dienoate) (Cationic Lipid A2), 9Z,12Z)-3-((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3- (diethylamino)propoxy)carbonyl)oxy)methyl)propyloctadeca-9,1 2-dienoate (Cationic Lipid A3), 1-(3-cholesteryl)-oxycarbonyl-aminomethylimidazole (CHIM), [(2-Morpholine-4-yl- ethylcarbamoyl)methyl]-carbamicacidcholesterylester (Chol-C3N-Mo2), [(2-Morpholine-4- yl-ethylcarbamoyl)-ethyl]-carbamicacidcholesterylesterChol-D MC3N-Mo2[1-Methyl-2-(2- morpholine-4-yl-ethylcarbamoyl)-propyl]-carbamicacidcholeste rylester (Chol-C4N-Mo2), 1,17-bis(2-octylcyclopropyl)heptadecan-9-yl4-(dimethylamino) butanoate (CL), heptatriaconta-6,9,28,31-tetraen-19-yl-4-(dimethylamino)-but anoate (CL01), cholesteryl3- (dimethylamino)propanoate (CL06), cholesteryl2-(dimethylamino)acetate (CL08), N,N- dimethyl-2,3-bis(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)propa n-1-amine (CL-1), N-methyl- 2-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)-N-(2-((((9Z,12Z)-o ctadeca-9,12-diene-1- yl)oxy)ethyl)ethan-1-amine (CL-11), (3R,4R)-3,4-bis(((Z)-hexadec-9-en-1-yl)oxy)-1- methylpyrrolidine(CompoundCL-12) (CL-12), 2-(Dimethylamino)-N-((6Z,9Z,28Z,31Z)- Heptatriconta-6,9,28,31-tetraen-19-yl)acetamide (CL-13), 3-(Dimethylamino)propane-1,2- diyl(9Z,9'Z,12Z,12'Z)-bis(octadeca-9,12-dienoate) (CL-14), (9Z,12Z)-di((9Z,12Z)-octadeca- 9,12-dien-1-yl)amine (CL-15), 7-Hydroxy7-(4-((1-methylpiperidine-4- carbonyl)oxy)butyl)tridecane-1,13-diyldidodecanoate (CL15B6), 7-Hydroxy7-(4-((1- methylpiperidine-4-carbonyl)oxy)butyl)tridecane-1,13-diyldit etradecanoate (CL15C6), 7- Hydroxy7-(4-((1-methylpiperidine-4-carbonyl)oxy)butyl)tridec ane-1,13-diyldipalmitate (CL15D6), 7-Hydroxy7-(4-((1-methylpiperidine-4-carbonyl)oxy)butyl)trid ecane-1,13- diyldioleate (CL15H6), Bis(2-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)ethyl)amine (CL-16), (9Z,12Z)-N-Methyl-N-(2-(((9Z,12Z)-octadeca-9,12-dien-1-yl)ox y)ethyl)octadeca-9,12-dien- 1-amine (CL-17), (9Z,12Z)-N-(3-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)propyl) octadeca- 9,12-dien-1-amine (CL-18), (1-Methylpiperidin-3-yl)methyldi((11Z,14Z)-icosa-11,14-dien- 1- yl)carbamate (CL-19), N-methyl-N,N-bis(2-((Z)-hexadec-9-enyloxy)ethyl)amine (CL-2), (13Z,16Z)-N,N-Dimethyl-4-((9Z,12Z)-octadeca-9,12-dien-1-yl)d ocosa-3,13,16-trien-1-amine (CL-20), (S)-2-Amino-3-hydroxy-N,N-bis(2-(((Z)-octadeca-9-en-1- yl)oxy)ethyl)propanamide (CL-21), C2:N,N-dihexadecyl-N'-(3- triethoxysilylpropyl)succinamide (CL3), trans-1-Methyl-3,4-bis((((Z)-octadec-9-en-1- yl)oxy)methyl)pyrrolidine (CL-3), trans-1-methylpyrrolidine-3,4- diyl)bis(methylene)(9Z,9'Z,12Z,12'Z)-bis(octadeca-9,12-dieno ate) (CL-4), 7-(4- (Diisopropylamino)butyl)-7-hydroxytridecane-1,13-diylditetra decanoate (CL4C6), 7-(4- (Diisopropylamino)butyl)-7-hydroxytridecane-1,13-diyldipalmi tate (CL4D6), 11-(4- (Diisopropylamino)butyl)-11-hydroxyhenicosane-1,21-diyldiole ate (CL4H10), 7-(4- (Diisopropylamino)butyl)-7-hydroxytridecane-1,13-diyldioleat e (CL4H6), 9-(4- (Diisopropylamino)butyl)-7-hydroxyheptadecane-1,17-diyldiole ate (CL4H8), (6Z,9Z,28Z,31Z)-Heptatriaconta-6,9,28,31-tetraen-19-yl4-(dim ethylamino)butanoate (CL-5), 2-(Dimethylamino)-N-(2-(((Z)-octadeca-9-en-1-yl)oxy)ethyl)-N -((9Z,12Z)-octadeca-9,12- diene-1-yl)acetamide (CL-53), 3-((2-(((Z)-octadeca-9-en-1-yl)oxy)ethyl)((9Z,12Z)-octadeca- 9,12-dien-1-yl)amino)propane-1-All (CL-54), 1-Methyl-3,3-bis((((9Z,12Z)-octadeca-9,12- dien-1-yl)oxy)methyl)azetidine (CL-55), 1-Methyl-3,3-bis(2-(((9Z,12Z)-octadeca-9,12-dien- 1-yl)oxy)ethyl)azetidine (CL-56), 1-Methyl-3,3-bis(2-(((9Z,12Z)-octadeca-9,12-dien-1- yl)oxy)propyl)azetidine (CL-57), 2-(3,3-di((9Z,12Z)-octadeca-9,12-dien-1-yl)azetidin-1- yl)ethan-1-ol (CL-58), 2-(3,3-di((9Z,12Z)-octadeca-9,12-dien-1-yl)azetidin-1-yl)pro pan-1-ol (CL-59), 3-(Di((9Z,12Z)-octadeca-9,12-dien-1-yl)amino)propan-1-o (CL-6), 3- (Dimethylamino)propyl3,3-di((9Z,12Z)-octadeca-9,12-dien-1-yl )azetidine-1-carboxylate (CL-60), 2-(Di((Z)-octadeca-9-en-1-yl)amino)ethane-1-ol (CL-61), 3-(Di((Z)-octadeca-9-en- 1-yl)amino)propan-1-ol (CL-62), (11Z,14Z)-2-((Dimethylamino)methyl)-2-((9Z,12Z)- octadeca-9,12-dien-1-yl)icosa-11,14-dien-1-ol (CL-63), (11Z,14Z)-2-(Dimethylamino)-2- ((9Z,12Z)-octadeca-9,12-dien-1-yl)icosa-11,14-dien-1-ol (CL-64), 3-(Dimethylamino)-2,2- bis((((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)methyl)propan-1-o l (CL-65), (9Z,12Z)-N-(2- (((Z)-Octadeca-9-en-1-yl)oxy)ethyl)octadeca-9,12-dien-1-amin e (CL-7), 1-Methyl-3,3- di((9Z,12Z)-octadeca-9,12-dien-1-yl)azetidine (CL-8), N,2-Dimethyl-1,3-bis(((9Z,12Z)- octadeca-9,12-dien-1-yl)oxy)propan-2-amine (CL-9), 3-Dimethylamino-2-(Cholest-5-en-3B- oxybutan-4-oxy)-1-(cis,cis-9,12-octadecadienoxy)propane (CLinDMA), 2-[5′-(cholest-5-en- 3-oxy)-3′-oxapentoxy)-3-dimethy-1-(cis,cis-9′,12′-octa decadienoxy)propane (CpLinDMA), cetyltrimethylammoniumbromide (CTAB), l^-Diarachidonyloxy-^TV-dimethy^-propyl-S- amine (DAraDMA), 0,0'-ditetradecanoyl-N-(α- trimethylammonioacetyl)diethanolaminechloride (DC-6-14), 3β-[N-(N′,N′- dimethylaminoethane)carbamoyl]cholesterol (DC-Chol), dimethyldioctadecylammonium (DDA), dimethyldioctadecylammoniumbromide (DDA ), N,N-distearyl-N,N- dimethylammoniumbromide (DDAB), 1,2-Didocosahexaenyloxy-(7V,N-dimethyl)-propyl-3- amine (DDocDMA), N-(2-(dimethylamino)ethyl)-4,5-bis(dodecylthio)pentanamide (DEDPA), 3-Dimethylamino-2-(Cholest-5-en-3β-oxypent-3-oxa-an-5-oxy)- 1-(cis,cis-9,12- octadecadienoxy)propane (DEG-CLinDMA), 1,6-DileoylTriethylenetetramide (dio-TETA), Nl,N19-bis((S,23E,25E,27E,29E)-16-((2E,4E,6E,8E)-3,7-dimethy l-9-(2,6,6-trimethylcyclo- hex-1-en-1-yl)nona-2,4,6,8-tetraenamido)-24,28-dimethyl-15,2 2-dioxo-30-(2,6,6- trimethylcyclohex-1-en-1-yl)-4,7,10-trioxa-14,21-diazatriaco nta-23,25,27,29-tetraen-1-yl)- 4,7,10,13,16-pentaoxanonadecane-1,19-diamide (diVA-PEG-diVA), DiLin-N- Methylpiperazine (DL-033), DiLin-N,N-DimethylGlycine (DL-036), Dioleyl-N,N- DimethylGlycine (DL-048), 3-((1,3-bis(((9Z,12Z)-octadeca-9,12-dienoyl)oxy)propan-2- yl)amino)propanoicacid (DLAPA), 1,2-dilinolenyloxy-3-dimethylaminopropane (DLenDMA), 1-Linoleoyl-2-linoleyloxy-3-dimethylaminopropane (DLin-2-DMAP), 3-(N,N- Dilinoleylamino)-1,2-propanediol (DLinAP), 1,2-N,N′-Dilinoleylcarbamyl-3- dimethylaminopropane (DLincarbDAP), 1,2-Dilinoleoylcarbamyl-3-dimethylaminopropane (DLinCDAP), 1,2-Dilinoleylcarbamoyloxy-3-dimethylaminopropane (DLin-C-DAP), 1,2- Dilinoleyoxy-3-(dimethylamino)acetoxypropane (DLin-DAC), 1,2-Dilinoleoyl-3- dimethylaminopropane (DLinDAP), 1,2-DiLinoleyloxy-N,N-dimethylaminopropane (DLinDMA ), 1,2-dilinoleyloxy-3-dimethylaminopropane (DLinDMA 1), 1,2-Dilinoleyloxo- 3-(2-N,N-dimethylamino)ethoxypropane (DLin-EG-DMA), dilinoleoyl-4-aminobutyricacid (DLinFAB), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-K-C2-DMA), 2,2-Dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA), 1,2-Dilinoleyoxy-3- morpholinopropane (DLin-MA), (6Z,9Z,28Z,31Z)-heptatriacont-6,9,28,31-tetraene-19-yl4- (dimethylamino)butanoate (DLin-MC3-DMA), 1,2-Dilinoleyloxy-3-(N- methylpiperazino)propane (DLinMPZ), 1,2-Dilinoleyloxy-3-(N-methylpiperazino)propane (DLin-MPZ), Dilinoleyloxy3-piperidinopropylamine (DLinPip), 1.2Dilinoleyloxy3-(3'- hvdroxypiperidino)-propylamine (DLinPip-3OH), 1,2Dilinoleyloxy3-(4'-hvdroxypiperidino)- propylamine (DLinPip-4OH), 1,2-Dilinoleyloxy-3-hvdroxypropane (DLinPO), 1,2- Dilinoleylthio-3-dimethylaminopropane (DLin-S-DMA), 1,2-Dilinoleoyl-3- trimethylaminopropane (DLinTAP), 1,2-Dilinoleoyl-3-trimethylaminopropanechloridesalt (DLin-TAP.Cl), 1,2-Dilinoleyloxy-3-trimethylaminopropane (DLinTMA), 1,2-Dilinoleyloxy- 3-trimethylaminopropanechloridesalt (DLin-TMA.Cl), 3-((1,3-bis(((9Z,12Z.15Z)-octadeca- 9,12,15-trienoyl)oxy)propan-2-yl)amino)propanoicacid (DLLAPA), 1,2Dilinoleyloxy3- (N,NdimethyD-propylamme (DLmDEA), 1,2-Dilauroyl-sn-Glicero-3-Phosphoethanolamine (DLPE), 1,2-Dilauroyl-sn-Glicero-3-Glycerol (DLPG), N,N-Dimethyl-3,4- dioleyloxybenzylamine (DMOBA), dimyristoylphosphatidylserine (DMPS), N-[1-(2,3- dimyristyloxy)propyl]-N,N-dimethyl-N-(2-hydroxyethyl)ammoniu mbromide (DMRIE), 1,2- Dimyristyloxypropyl-3-dimethyl-hydroxyethylammoniumbromide (DMRIE1), 1,2- dimyristoyl-3-trimethylammoniumpropane (DMTAP), 3-(N,N-Dioleylamino)-1,2-propanedio (DOAP), 3-((1,3-bis(oleoyloxy)propan-2-yl)amino)propanoicacid (DOAPA), 1,2-N,N′- dioleylcarbamyl-3-dimethylaminopropane (DOcarbDAP), 1,2-Dioleoylcarbamyl-3- Dimethylammonium-propane (DOCDAP), N,N-dioleyl-N,N-dimethylammoniumchloride (DODAC), 1,2-Dioleoyl-3-Dimethylammonium-propane (DODAP), N,N- dihydroxyethylΝ,Ν-dioctadecylammoniumchloride (DODEAC), N,N-dimethyl-2,3- dioleyloxypropylamine (DODMA), dioleoyl-4-aminobutyricacid (DOFAB), Dioctadecylamidoglycylspermine (DOGS), 1,2-Dioleoyl-3-methyl-(methoxycarbonyl- ethyl)ammonium-Propane (DOMCAP), 1,2-Dioleoyl-3-N-pyrrolidine-propane (DOP5P), 1,2- Dioleoyl-3-N-pyrridinium-propane,bromidesalt (DOP6P), 1,2-dioleoyl-3-dimethyl- hydroxyethylammoniumbromide (DORI), 1,2-dioleyloxypropyl-3-dimethyl- hydroxyethylammoniumbromide (DORIE), 1,2-dioleyloxypropyl-3-dimethyl- hydroxybutylammoniumbromide (DORIE-HB), 1,2-dioleyloxypropyl-3-dimetyl- hydroxypropylammoniumbromide (DORIE-HP), 1,2-dioleyloxypropyl-3-dimethyl- hydroxypentylammoniumbromide (DORIE-Hpe), 2,3-dioleyloxy-N-[2(spermine- carboxamido)ethyl]-N,N-dimethyl-1-propanaminiumtrifluoroacet ate (DOSPA), 1,3- dioleoyloxy-2-(6-carboxy-spermyl)-propylamide (DOSPER), N-(1-(2,3-dioleoyloxy)propyl)- N,N,N-trimethylammoniumchloride (DOTAP), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP1), N-[5'-(2',3'-dioleoyl)uridine]-Ν',Ν',Ν'-trimethylammonium tosylate (DOTAU), 1- [2-(9(Z)-octadecenoyloxy)ethyl]-2-(8(Z)-heptadecenyl-3-(2- hydroxyethyl)imidazoliniumchloride (DOTIM), N-(1-(2,3-dioleyloxy)propyl)-N,N,N- trimethylammoniumchloride (DOTMA), dioleylphosphatidyluridinephosphatidylcholine (DOUPC), 1,2-Diphvtanyloxy-W.N-dimemyl)-butyl-4-amme (DPan-C2-DMA), 1,2- Diphytanyloxy-3-(iV,7V-dimethy1)-propylamine (DPanDMA), 2,3-bis(dodecylthio)propyl(2- (dimethylamino)ethyl)carbamate (DPDEC), dipalmitoyl-4-aminobutyricacid (DPFAB), 1,2- dipalmityloxypropyl-3-dimethyl-hydroxyethylammoniumbromide (DPRIE), 1,2-dipalmitoyl- 3-trimethylammoniumpropane (DPTAP), 1-[2-(hexadecanoyloxy)ethyl]-2-pentadecyl-3-(2- hydroxyethyl)imidazoliniumchloride (DPTIM), 3-((1,3-bis(stearoyloxy)propan-2- yl)amino)propanoicacid (DSAPA), distearyldimethylammonium (DSDMA), 1,2-distearloxy- N,N-dimethylaminopropane (DSDMA1), 1,2-disteryloxypropyl-3-dimethyl- hydroxyethylammoniumbromide (DSRIE), 1,2-disteroyl-3-trimethylammoniumpropane (DSTAP), ditetradecyltrimethylammonium (DTDTMA), 1,2-dioleoyl-sn-glycero-3- ethylphosphocholine (EDOPC), N2-[N2,N5-bis(3-aminopropyl)-L-ormithyl]-N,N- dioctadecyl-L-glutaminetetrahydrotrifluoroacetate (GC33), Cholest-5-en-3-ol(3P)-,3-[(3- aminopropyl)[4-[(3-aminopropyl)amino]butyl]carbamate] (GL67), glycerylmono-oleate (GMO), Guanidino-dialkyl-carboxylicacid (GUADACA), 2-(bis(2- (tetradecanoyloxy)ethyl)amino)-N-(2-hydroxyethyl)-N,N-dimeth yl-2-oxoethan- aminiumbromide (HEDC), 2,2'-(tert-butoxycarbonylazanediyl)bis(ethane-2,1- diyl)ditetradecanoate (HEDC-BOC-TN), 1-(2-(((3S,10R,13R)-10,13-dimethyl-17-((R)-6- methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetra decahydro-1H- cyclopenta[a]phenanthren-3-yldisulfanyl)ethyl)guanidine (HGT4002), (15Z,18Z)-N,N- dimethyl-6-(9Z,12Z)-octadeca-9,12-dien-1-yl)tetracosa-15,18- dien-1-amine (HGT5000), (15Z,18Z)-N,N-dimethyl-6-((9Z,12Z)-octadeca-9,12-dien-1-yl)t etracosa-4,15,18-trien-1- amine (HGT5001), Histaminyl-Cholesterolhemisuccinat (HisChol), histidinylcholesterolhemisuccinate (Hist-Chol), HydroSoyPC (HSPC), imidazolecholesterolester (ICE), 3-(didodecylamino)-N1,N1,4-tridodecyl-1- piperazineethanamine (KL10), N1-[2-(didodecylamino)ethyl]-N1,N4,N4-tridodecyl-1,4- piperazinediethanamine (KL22), 14,25-ditridecyl-15,18,21,24-tetraaza-octatriacontane (KL25), N,N-di-n-lctradecyl,N-methyl-N-(2-guanidinyl)cthylammonium (Lipid 1), N,N-di-n- octadecyl,N-mcthyl-N-(2-guanidinyl)cthylammoniumchloride (Lipid 2), 3-((4,4- bis(octyloxy)butanoyl)oxy)-2-((((3- (diethylamino)propoxy)carbonyl)oxy)methyl)propyl(9Z,12Z)-oct adeca-9,12-dienoate (Lipid A), (9Z,12Z)-3-((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3- (diethylamino)propoxy)carbonyl)oxy)methyl)propyloctadeca-9,1 2-dienoate (Lipid A1), 2,2- Dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (Lipid A2), ((5-((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(octan e-8,1-diyl)bis(decanoate) (Lipid B), 2-((4-(((3- (dimethylamino)propoxy)carbonyl)oxy)hexadecanoyl)oxy)propane -1,3-diyl9Z,9'Z,12Z,12'Z)- bis(octadeca-9,12-dienoate) (Lipid C), 3-(((3-(dimethylamino)propoxy)carbonyl)oxy)-13- (octanoyloxy)tridecyl3-octylundecanoate (Lipid D), (6Z,16Z)-12-((Z)-dec-4-en-1-yl)docosa- 6,16-dien-11-yl5-(dimethylamino)pentanoate (Lipid I), Dioctadecyl-(2-hydroxy1-3- propylamino)aminopolylysine (Lipid T), (3-((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31- tetraen-19-yloxy)-N,N-dimethylpropan-1-amine (MC3 Ether), describedinU.S.ProvisionalApplicationNo.61/384,050 (MC3 Thioester), (4- ((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yloxy)- N,N-dimethylbutan-1-amine (MC4 Ether), 3-((2-(((9Z,12Z)-octadeca-9,12-dienoyl)oxy)ethyl)amino)propa noicacid (MLAPA), 3-((2-(((9Z,12Z,15Z)-octadeca-9,12,15-trienoyl)oxy)ethvnamin o)propanoicacid (MLLAPA), mon-omycolylglycerol (MMG), 3-((2-(oleoyloxy)ethyl)amino)propanoicacid (MOAPA), 4-(2-Aminoethyl)-Morpholino-Cholesterolhemisuccinat (MoChol), 1,2-Dioleoyl- 3-N-morpholine-propane (MoDO), Methylpyridiyl-dialkyl-carboxylicacid (MPDACA), monopalmitoylphosphatidylcholin (MPPC), 3-((2-(stearoyloxy)ethyl)amino)propanoicacid (MSAPA), N1-[2-((lS)-1-[(3-aminopropyl)amino]-4-[di(3-amino- propyl)amino]butylcarboxamido)ethyl]-3,4-di[oleyloxy]-benzam ide (MVL5), 2-({8-[(3β)- cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-[(9Z,12Z)-oct adeca-9,12-dien-1- yloxy]propan-1-amine (Octyl-CLinDMA), (2R)-2-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)- N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-1 -amine (Octyl-CLinDMA (2R)), phosphatidylcholines (PC), 1,3-Bis-(1,2-bis-tetradecyloxy-propyl-3- dimemylethoxyammoniumbromide)-propane-2-ol (PCL-2), palmitoyi-oieoyl-nor-arginine (PONA), stearylamine (STA), 2-(((tert-Butyldimethylsilyl)oxy)methyl)-2- (hydroxymethyl)propane-1,3-diol (Synthesis Example 1 (A)), 3-((tert- Butyl(dimethyl)silyl)oxy)-2,2-bis(((9Z)-tetradec-9-enoyloxy) methyl)propyl(9Z)-tetradec-9- enoate (Synthesis Example 1 (B)), 3-Hydroxy-2,2-bis(((9Z)-tetradec-9- enoyloxy)methyl)propyl(9Z)-tetradec-9-enoate (Synthesis Example 1 (C)), 3-((4- (Dimethylamino)butanoyl)oxy)-2,2-bis(((9Z)-tetradec-9-enoylo xy)methyl)propyl(9Z)- tetradec-9-enoate (Synthesis Example 1 (D)), 3-(5-(bis(2-hydroxydodecyl)amino)pentan-2- yl)-6-(5-((2-hydroxydodecyl)(2-hydroxyundecyl)amino)pentan-2 -yl)-1,4-dioxane-2,5-dione) (Target 24), trehalose6'6'-dibehenate (TDB), 1,1'-(2-(4-(2-((2- (bis(2hydroxydodecyl)amino)ethyl)(2-hydroxydodecyl)amino)eth yl)piperazin-1- yl)ethylazanediyl)didodecan-2-ol (Tech G1), 3-((1,3-bis(((9Z,12Z)-octadeca-9,12- dienoyl)oxy)-2-((((9Z,12Z)-octadeca-9,12-dienoyl)oxy)methyl) propan-2- yl)amino)propanoicacid (TLAPA), (l-(2,3-linoleyloxypropoxy)-2-(linoleyloxy)-(7V,Λ/- dimethyl)-propyl-3-amine) (TLinDMA), 3-((1,3-bis(((9Z.12Z.15Z)-octadeca-9.12.15- trienoyl)oxy)-2-((((9Z.12Z.15E)-octadeca-9,12,15-trienoyl)ox y)methyl)propan-2- yl)amino)propanoicacid (TLLAPA), N-(α-trimethylammonioacetyl)-didodecyl-D- glutamatechloride (TMAG), 3-((1,3-bis(((Z)-octadec-9-enoyl)oxy)-2-((((Z)-octadec-9- enoyl)oxy)methyl)propan-2-yl)amino)propanoicacid (TOAPA), 3-((1,3-bis(stearoyloxy)-2- ((stearoyloxy)methyl)propan-2-yl)amino)propanoicacid (TSAPA), 1,N19- bis((16E,18E,20E,22E)-17,21-dimethyl-15-oxo-23-(2,6,6-trimet hylcyclohex-1-en-1-yl)- 4,7,10-trioxa-14-azatricosa-16,18,20,22-tetraen-1-yl)-4,7,10 ,13,16-pentaoxanonadecane- 1,19-diamide (VA-PEG-VA), 2,2-Dillinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (XTC), disclosedinNon-PatentLiterature11 (YSK05), 1,2-di-γ-linolenyloxy-N,N- dimethylaminopropane (γ-DLenDMA), a-D-Tocopherolhemisuccinoyl, (9Z,9,Z,12Z,12,Z)-2- ((2-(((3-(dimethylamino)propoxy)carbonyl)oxy)tetradecanoyl)o xy)propane-1,3- diylbis(octadeca-9,12-dienoate), 2-(((13Z,16Z)-4-(((3- (diethylamino)propoxy)carbonyl)oxy)docosa-13,16-dienoyl)oxy) propane-1,3- diyldioctanoate, 2-(((13Z,16Z)-4-(((3-(dimethylamino)propoxy)carbonyl)oxy)doc osa-13,16- dienoyl)oxy)propane-1,3-diyldioctanoate, 2-((4-(((3- (ethyl(methyl)amino)propoxy)carbonyl)oxy)hexadecanoyl)oxy)pr opane-1,3-diyldioctanoate, 2-((4-(((3-(ethyl(methyl)amino)propoxy)carbonyl)oxy)hexadeca noyl)oxy)propane-1,3- diylbis(decanoate), 2-((4-(((3- (diethylamino)propoxy)carbonyl)oxy)hexadecanoyl)oxy)propane- 1,3-diylbis(decanoate), 2- (10-dodecyl-3-ethyl-8,14-dioxo-7,9,13-trioxa-3-azaicosan-20- yl)propane-1,3-diyldioctanoate, 2-(((4-(dimethylamino)butanoyl)oxy)methyl)-2-((octanoyloxy)m ethyl)propane-1,3- diyl(9Z,9'Z)bis-tetradec-9-enoate, (9Z,9'Z,12Z,12'Z)-2-(((1-(cyclopropylmethyl)piperidine-4- carbonyl)oxy)methyl)propane-1,3-diylbis(octadeca-9,12-dienoa te), ((2-(((1- isopropylpiperidine-4-carbonyl)oxy)methyl)-1,4-phenylene)bis (oxy))bis(octane-8,1- diyl)bis(decanoate), 2-((4-(((3- (ethyl(methyl)amino)propoxy)carbonyl)oxy)hexadecanoyl)oxy)pr opane-1,3- diyldidodecanoate, 2-((4-(((3- (diethylamino)propoxy)carbonyl)oxy)hexadecanoyl)oxy)propane- 1,3-diyldidodecanoate, 2- ((4-(((3-(dimethylamino)propoxy)carbonyl)oxy)hexadecanoyl)ox y)propane-1,3- diyldidodecanoate, 2-((4-(((3- (ethyl(methyl)amino)propoxy)carbonyl)oxy)hexadecanoyl)oxy)pr opane-1,3- diylditetradecanoate, 2-((4-(((3- (dimethylamino)propoxy)carbonyl)oxy)hexadecanoyl)oxy)propane -1,3-diylditetradecanoate, 2-((4-(((3-(diethylamino)propoxy)carbonyl)oxy)hexadecanoyl)o xy)propane-1,3- diylditetradecanoate, (Z)-2-((4-(((3- (dimethylamino)propoxy)carbonyl)oxy)hexadecanoyl)oxy)propane -1,3-diyldioleate, (9Z,9,Z,12Z,12,Z,15Z,15,Z)-2-((4-(((3- (dimethylamino)propoxy)carbonyl)oxy)hexadecanoyl)oxy)propane -1,3-diylbis(octadeca- 9,12,15-trienoate), (9Z,9,Z,12Z,12,Z)-2-((4-(((3- (diethylamino)propoxy)carbonyl)oxy)hexadecanoyl)oxy)propane- 1,3-diylbis(octadeca-9,12- dienoate), (9Z,9,Z,12Z,12,Z)-2-((4-(((3- (dimethylamino)propoxy)carbonyl)oxy)hexadecanoyl)oxy)propane -1,3-diylbis(octadeca- 9,12-dienoate), N,N,N-trimethyl-5-oxo-5-(3-((3-pentyloctanoyl)oxy)-2,2-bis(( (3- pentyloctanoyl)oxy)methyl)propoxy)pentane-1-Aminiumiodide3-( (5- (dimethylamino)pentanoyl)oxy)-2,2-bis(((3-pentyloctanoyl)oxy )methyl)propyl3- pentyloctanoate, 3-dimethylaminopropylcarbonate(9Z,12Z)-octacosa-19,22-dien-1 1-yl, 2- (((N,N-dimethyl-β-alanyl)oxy]methyl}-2-[(octanoyloxy)methyl )propane-1,3-diyl(9Z,9'Z)bis- tetradec-9-enoate, ΟΊ,O1-(2-(7-dodecyl-14-methyl-3,9-dioxo-2,4,8,10-tetraoxa- 14- azapentadecyl)propane-1,3-diyl)8-dimethyldioctanedioate, 8-dimethylΟΊ,01-(2-(((1- methylpyrrolidine-3-carbonyl)oxy)methyl)propane-1,3-diyl)dio ctanedioate, 1-(3-((6,6-bis((2- propylpentyl)oxy)hexanoyl)oxy)-2-(((1,4-dimethylpiperidine-4 - carbonyl)oxy)methyl)propyl)8-methyloctanedioate, (9Z,12Z)-5-(((3- (dimethylamino)propoxy)carbonyl)oxy)-7-octylpentadecyloctade ca-9,12-dienoate, 5-(((3- (dimethylamino)propoxy)carbonyl)oxy)-7-octylpentadecyloctano ate, 1-(3-((6,6-bis((2- propylpentyl)oxy)hexanoyl)oxy)-2-(((1,4-dimethylpiperidine-4 - carbonyl)oxy)methyl)propyl)10-octyldecanedioate, 3-(((3- (dimethylamino)propoxy)carbonyl)oxy)-5-octyltridecyldecanoat e, 1-(16-(((4,4- bis(octyloxy)butanoyl)oxy)methyl)-9-dodecyl-2-methyl-7,13-di oxo-6,8,12,14-tetraoxa-2- azaheptadecan-17-yl)8-methyloctanedioate, 3-((5-(dimethylamino)pentanoyl)oxy)-2,2- bis(((9Z)-tetradec-9-enoyloxy)methyl)propyl(9Z,12Z)-octadec- 9,12-dienoate, 3-((5- (Dimethylamino)pentanoyl)oxy)-2,2-bis(((3-pentyloctanoyl)oxy )methyl)propyl3- pentyloctanoate, (9Z,9'Z,12Z,12'Z)-2-(((3-(diethylamino)propanoyl)oxy)methyl) propane-1,3- diylbis(octadeca-9,12-dienoate), ((2-(((4-(dimethylamino)butanoyl)oxy)methyl)-1,4- phenylene)bis(oxy))bis(octane-8,1-diyl)bis(decanoate), 1-(3-((4,4- bis(octyloxy)butanoyl)oxy)-2-(((1-methylpyrrolidine-3-carbon yl)oxy)methyl)propyl)8- methyloctanedioate, 3-((4,4-bis(octyloxy)butanoyl)oxy)-2-((palmitoyloxy)methyl)p ropyl1- methylpyrrolidine-3-carboxylate, 3-((4,4-bis(octyloxy)butanoyl)oxy)-2- ((tetradecanoyloxy)methyl)propyl1-methylpyrrolidine-3-carbox ylate, 3-(((3- (dimethylamino)propoxy)carbonyl)oxy)-13-(octanoyloxy)tridecy l9-pentyltetradecanoate, 3- ((4,4-bis(octyloxy)butanoyl)oxy)-2-((dodecanoyloxy)methyl)pr opyl1-methylpyrrolidine-3- carboxylate, 3-(((3-(dimethylamino)propoxy)carbonyl)oxy)-13-hydroxytridec yl9- pentyltetradecanoate, 3-(((3-(dimethylamino)propoxy)carbonyl)oxy)-13- (octanoyloxy)tridecyl7-hexyltridecanoate, 2-(5-(3-((1-methylpyrrolidine-3-carbonyl)oxy)-2- ((tetradecanoyloxy)methyl)propoxy)-5-oxopentyl)propane-1,3-d iyldioctanoate, 3-(((3- (dimethylamino)propoxy)carbonyl)oxy)-13-(octanoyloxy)tridecy l5-heptyldodecanoate, 2-(5- (3-((1-methylpyrrolidine-3-carbonyl)oxy)-2-((palmitoyloxy)me thyl)propoxy)-5- oxopentyl)propane-1,3-diyldioctanoate, 3-(((3-(dimethylamino)propoxy)carbonyl)oxy)-13- hydroxytridecyl5-heptyldodecanoate, 2-(((1-methylpyrrolidine-3- carbonyl)oxy)methyl)propane-1,3-diylbis(6,6-bis(octyloxy)hex anoate), (9Z,12Z)-3-(((3- dimethylamino)propoxy)carbonyl)oxy)-13-(octanoyloxy)tridecyl octadeca-9,12-dienoate, 3- ((5-(dimethylamino)pentanoyl)oxy)-2,2-bis(((9Z)-tetradec-9-e noyloxy)methyl)propyl(9Z)- octadec-9-enoate, 2-(10-dodecyl-3-ethyl-8,14-dioxo-7,9,13-trioxa-3-azanonadeca n-19- yl)propane-1,3-diyldioctanoate, ((2-(((1-methylpiperidine-4-carbonyl)oxy)methyl)-1,4- phenylene)bis(oxy))bis(octane-8,1-diyl)bis(decanoate), 2-(((3- (dimethylamino)propanoyl)oxy)methyl)propane-1,3-diylbis(4,4- bis(octyloxy)butanoate), (9Z,12Z)-2-(((11Z,14Z)-2-((3-(dimethylamino)propanoyl)oxy)ic osa-11,14-dien-1- yl)oxy)ethyloctadeca-9,12-dienoate, 2-(((1,3-dimethylpyrrolidine-3- carbonyl)oxy)methyl)propane-1,3-diylbis(4,4-bis(octyloxy)but anoate), (13Z,16Z)-4-(((3- (dimethylamino)propoxy)carbonyl)oxy)docosa-13,16-dien-1-ylhe ptadecan-9-ylsuccinate, 2,2- bis(heptyloxy)ethyl3-((3-ethyl-10-((9Z,12Z)-octadeca-9,12-di en-1-yl)-8,15-dioxo-7,9,14- trioxa-3-azaheptadecan-17-yl)disulfanyl)propanoate, 2-(((1-methylpyrrolidine-3- carbonyl)oxy)methyl)propane-1,3-diylbis(4,4-bis(octyloxy)but a, 1-(3-((1,3- dimethylpyrrolidine-3-carbonyl)oxy)-2-(((9Z,12Z)-octadeca-9, 12- dienoyloxy)methyl)propyl)10-octyldecanedioate, (13Z,16Z)-4-(((3- (diethylamino)propoxy)carbonyl)oxy)docosa-13,16-dien-1-yl2,2 -bis(heptyloxy)acetate, (13Z,16Z)-4-(((2-(dimethylamino)ethoxy)carbonyl)oxy)docosa-1 3,16-dien-1-yl2,2- bis(heptyloxy)acetate, Aceticacid(20,23R)-2-methyl-9-[(9Z,12Z)-octadeca-9,12-dien-1 -yl]-7- oxo-6,8,11-trioxa-2-azanonacosa-20-En-23-yl3-(dimethylamino) propylcarbonate(11Z,14Z)- 1-{[(9Z,12R)-12-hydroxyoctadec-9-en-1-yl], (12Z,15Z)-1-((((9Z,12Z)-octadeca-9,12-dien-1- yloxy)carbonyl)oxy)henicosa-12,15-dien-3-yl3-(dimethylamino) propanoate, (9Z,12Z)-3- ((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3- (dimethylamino)propyl)carbamoyl)oxy)methyl)propyloctadeca-9, 12-dienoate, (12Z,15Z)-3- ((4-(dimethylamino)butanoyl)oxy)henicosa-12,15-dien-1-yl9-pe ntyltetradecanoate, (9Z,12Z)- 3-((4,4-bis(octyloxy)butanoyl)oxy)-2-(((((1,2,2,6,6-pentamet hylpiperidin-4- yl)oxy)carbonyl)oxy)methyl)propyloctadeca-9,12-dienoate, (12Z,15Z)-3-((4- (dimethylamino)butanoyl)oxy)henicosa-12,15-dien-1-yl7-hexylt ridecanoate, (9Z,12Z)-3- ((4,4-bis(octyloxy)butanoyl)oxy)-2-(((((1-methylpiperidin-4- yl)methoxy)carbonyl)oxy)methyl)propyloctadeca-9,12-dienoate, (12Z,15Z)-3-((4- (dimethylamino)butanoyl)oxy)henicosa-12,15-dien-1-yl5-heptyl dodecanoate, (9Z,12Z)-3- ((4,4-bis(octyloxy)butanoyl)oxy)-2-(((((1-ethylpiperidin-4- yl)oxy)carbonyl)oxy)methyl)propyloctadeca-9,12-dienoate, (12Z,15Z)-3-((4- (dimethylamino)butanoyl)oxy)henicosa-12,15-dien-1-yl3-octylu ndecanoate,formatesalt, 3- ((5-(dimethylamino)pentanoyl)oxy)-2,2-bis(((9Z)-tetradec-9-e noyloxy)methyl)propyl(9Z)- hexadec-9-enoate, (9Z,12Z)-3-((4,4-bis(octyloxy)butanoyl)oxy)-2-(((((1-methyla zetidin-3- yl)oxy)carbonyl)oxy)methyl)propyloctadeca-9,12-dienoate, (9Z,12Z)-(12Z,15Z)-3-((3- (dimethylamino)propanoyl)oxy)henicosa-12,15-dien-1-yloctadec a-9,12-dienoate, 2-(((3- (diethylamino)propoxy)carbonyl)oxy)tetradecyl4,4-bis((2-ethy lhexyl)oxy)butanoate, (9Z,12Z)-3-((4,4-bis(octyloxy)butanoyl)oxy)-2-(((((1-methylp iperidin-4- yl)oxy)carbonyl)oxy)methyl)propyloctadeca-9,12-dienoate, (9Z,12Z)-3-((4,4- bis(octyloxy)butanoyl)oxy)-2-(((((1-methylpyrrolidin-3- yl)oxy)carbonyl)oxy)methyl)propyloctadeca-9,12-dienoate, (9Z,12Z)-3-(((2- (dimethylamino)ethoxy)carbonyl)oxy)pentadecyloctadeca-9,12-d ienoate, (9Z,12Z)-3-((4,4- bis(octyloxy)butanoyl)oxy)-2-((((3-(4-methylpiperazin-1- yl)propoxy)carbonyl)oxy)methyl)propyloctadeca-9,12-dienoate, 3- (Dimethylamino)propyltriacontan-11-ylcarbonateTriacontan-11- ol, (9Z,12Z)-3-((4,4- bis(octyloxy)butanoyl)oxy)-2-((((3-(pyrrolidin-1- yl)propoxy)carbonyl)oxy)methyl)propyloctadeca-9,12-dienoate, (9Z,12Z)-3-(((3- (ethyl(methyl)amino)propoxy)carbonyl)oxy)pentadecyloctadeca- 9,12-dienoate, 3-((4,4- bis(octyloxy)butanoyl)oxy)-2-(((9Z,12Z)-octadeca-9,12-dienoy loxy)methyl)propyl4- ((diethylamino)methyl)benzoate, (9Z,12Z)-3-(((3- (diethylamino)propoxy)carbonyl)oxy)pentadecyloctadeca-9,12-d ienoate, 3-((4,4- bis(octyloxy)butanoyl)oxy)-2-(((9Z,12Z)-octadeca-9,12-dienoy loxy)methyl)propyl3- ((dimethylamino)methyl)benzoate, (9Z,12Z)-3-(((3- (dimethylamino)propoxy)carbonyl)oxy)pentadecyloctadeca-9,12- dienoate, 3-((4,4- bis(octyloxy)butanoyl)oxy)-2-(((9Z,12Z)-octadeca-9,12-dienoy loxy)methyl)propyl1- methylpiperidine-3-carboxylate, 3-((4,4-bis(octyloxy)butanoyl)oxy)-2-(((9Z,12Z)-octadeca- 9,12-dienoyloxy)methyl)propyl1-methylpiperidine-4-carboxylat e, 3-((4,4- bis(octyloxy)butanoyl)oxy)-2-(((9Z,12Z)-octadeca-9,12-dienoy loxy)methyl)propyl1,4- dimethylpiperidine-4-carboxylate, 3-((4-(dimethylamino)butanoyl)oxy)-2,2-bis(((9Z)- tetradec-9-enoyloxy)methyl)propyl(9Z)-hexadec-9-enoate, 2-(10-dodecyl-3-ethyl-8,14-dioxo- 7,9,13-trioxa-3-azahexadecan-16-yl)propane-1,3-diyldioctanoa te, (9Z,9'Z,12Z,12'Z)-2-(((4- (piperidin-1-yl)butanoyl)oxy)methyl)propane-1,3-diylbis(octa deca-9,12-dienoate), 3-((4,4- bis(octyloxy)butanoyl)oxy)-2-(((9Z,12Z)-octadeca-9,12-dienoy loxy)methyl)propyl4- methylmorpholine-2-carboxylate, (2R)-3-((4,4-bis(octyloxy)butanoyl)oxy)-2-(((9Z,12Z)- octadeca-9,12-dienoyloxy)methyl)propyl1-methylpyrrolidine-2- carboxylate, (2S)-3-((4,4- bis(octyloxy)butanoyl)oxy)-2-(((9Z,12Z)-octadeca-9,12-dienoy loxy)methyl)propyl1- methylpyrrolidine-2-carboxylate, (9Z,9'Z,12Z,12'Z)-2-((((3- (diethylamino)propoxy)carbonyl)oxy)methyl)-2-(((9Z,12Z)-octa deca-9,12- dienoyloxy)methyl)propane-1,3-diylbis(octadeca-9,12-dienoate ), (9Z,12Z)-3-((4,4- bis(octyloxy)butanoyl)oxy)-2-(((((1-ethylpiperidin-3- yl)methoxy)carbonyl)oxy)methyl)propyloctadeca-9,12-dienoate, 3-((4,4- bis(octyloxy)butanoyl)oxy)-2-(((9Z,12Z)-octadeca-9,12-dienoy loxy)methyl)propyl1- (cyclopropylmethyl)piperidine-4-carboxylate, 3-((4,4-bis(octyloxy)butanoyl)oxy)-2- (((9Z,12Z)-octadeca-9,12-dienoyloxy)methyl)propyl1-isopropyl piperidine-4-carboxylate, (9Z,12Z)-3-((4,4-bis(octyloxy)butanoyl)oxy)-2-(((3- (dimethylamino)propanoyl)oxy)methyl)propyloctadeca-9,12-dien oate, 4- (dimethylamino)butylcarbonate(6Z,9Z,26Z,29Z)-pentatriaconta- 6,9,26,29-tetraen-18-yl, 3- ((6-(dimethylamino)hexanoyl)oxy)-2,2-bis(((9Z)-tetradec-9-en oyloxy)methyl)propyl(9Z)- tetradec-9-enoate, 2,5-bis((9Z,12Z)-octadeca-9,12-dienyloxy)benzyl3- (dimethylamino)propylcarbonate, (9Z,9'Z,12Z,12'Z)-2-(((4-(pyrrolidin-1- yl)butanoyl)oxy)methyl)propane-1,3-diylbis(octadeca-9,12-die noate), 3-(((3- (dimethylamino)propoxy)carbonyl)oxy)pentadecyl5-heptyldodeca noate, Aceticacid(7R,9Z)- 18-({[3-(dimethylamino)propyloxy]carbonyl}oxy)octacosa-9-en- 7-yl, 3-(((3- (dimethylamino)propoxy)carbonyl)oxy)pentadecyl9-pentyltetrad ecanoate, (9Z,12Z)-3-((6,6- bis(octyloxy)hexanoyl)oxy)-2-((((3- (diethylamino)propoxy)carbonyl)oxy)methyl)propyloctadeca-9,1 2-dienoate, 3-(((3- (dimethylamino)propoxy)carbonyl)oxy)pentadecyl7-hexyltridec- 6-enoate, (9Z,12Z)-3-(2,2- bis(heptyloxy)acetoxy)-2-((((2-(dimethylamino)ethoxy)carbony l)oxy)methyl)propyloctadeca- 9,12-dienoate, 3-(((3-(dimethylamino)propoxy)carbonyl)oxy)pentadecyl3-octyl undec-2- enoate, (9Z,12Z)-3-(((3-(diethylamino)propoxy)carbonyl)oxy)-2-(((5- heptyldodecanoyl)oxy)methyl)propyloctadeca-9,12-dienoate, 3-(((3- dimethylamino)propoxy)carbonyl)oxy)pentadecyl3octylundecanoa te, (9Z,12Z)-3-(((3- (diethylamino)propoxy)carbonyl)oxy)-2-(((9- pentyltetradecanoyl)oxy)methyl)propyloctadeca-9,12-dienoate, Diaceticacid(7R,9Z,26Z,29R)-18-({[3- (dimethylamino)propoxy]carbonyl}oxy)pentatriaconta-9,26-dien e-7,29-diyl, 3-(((3- (dimethylamino)propoxy)carbonyl)oxy)pentadecyl8,8-bis((2-pro pylpentyl)oxy)octanoate, (9Z,12Z)-3-(((3-(diethylamino)propoxy)carbonyl)oxy)-2-(((7- hexyltridecanoyl)oxy)methyl)propyloctadeca-9,12-dienoate, 3-(((3- (ethyl(methyl)amino)propoxy)carbonyl)oxy)pentadecyl8,8-bis(( 2- propylpentyl)oxy)octanoate, (9Z,12Z)-3-(((3-(diethylamino)propoxy)carbonyl)oxy)-2-(((3- octylundecanoyl)oxy)methyl)propyloctadeca-9,12-dienoate, 3-(((3- (diethylamino)propoxy)carbonyl)oxy)pentadecyl8,8-bis((2-prop ylpentyl)oxy)octanoate, 3- (((3-(diethylamino)propoxy)carbonyl)oxy)pentadecyl8,8-dibuto xyoctanoate, 3-((5- (dimethylamino)pentanoyl)oxy)-2,2-bis(((9Z)-tetradec-9-enoyl oxy)methyl)propyl(9Z)- tetradec-9-enoate, 3-(Dimethylamino)propylcarbonate(6Z,9Z,26Z,29Z)-pentatriacon tour- 6,9,26,29-tetraen-18-yl, 2,5-bis((9Z,12Z)-octadeca-9,12-dien-1-yloxy)benzyl3- (dimethylamino)propanoate, (9Z,9'Z,12Z,12'Z)-2-(((3-(4-methylpiperazin-1- yl)propanoyl)oxy)methyl)propane-1,3-diylbis(octadeca-9,12-di enoate), 3-(((3- (diethylamino)propoxy)carbonyl)oxy)pentadecyl8,8-bis(octylox y)octanoate, 3- (Dimethylamino)propyloctacosane-11-ylcarbonate, 2,4-bis((9Z,12Z)-octadeca-9,12- dienyloxy)benzyl4-(dimethylamino)butanoate, (9Z,12Z)-3-(((3- (diethylamino)propoxy)carbonyl)oxy)-2-(((2-heptylundecanoyl) oxy)methyl)propyloctadeca- 9,12-dienoate, 3-(((3-(diethylamino)propoxy)carbonyl)oxy)pentadecyl6,6-bis( (2- ethylhexyl)oxy)hexanoate, 2-((((3-(dimethylamino)propoxy)carbonyl)oxy)methyl)propane- 1,3-diylbis(2-heptylundecanoate), 3-(((3-(diethylamino)propoxy)carbonyl)oxy)pentadecyl6,6- bis(hexyloxy)hexanoate, 4-methyl-2,5-bis((9Z,12Z)-octadeca-9,12-dien-1-yloxy)benzyl4 - (dimethylamino)butanoate, 3-(((3-(diethylamino)propoxy)carbonyl)oxy)pentadecyl6,6- bis(octyloxy)hexanoate, 4-(dimethylamino)butyl4-methyl-2,5-bis((9Z,12Z)-octadeca-9,1 2- dienyloxy)benzylcarbonate, 3-(((3-(dimethylamino)propoxy)carbonyl)oxy)pendadecyl4,4- bis((2-propylpentyl)oxy)butanoate, 2-(12-dodecyl-3-ethyl-8,14-dioxo-7,9,13-trioxa-3- azaoctadecan-18-yl)propane-1,3-diyldioctanoate, 2-(5-oxo-5-((3-(((3-(piperidin-1- yl)propoxy)carbonyl)oxy)pentadecyl)oxy)pentyl)propane-1,3-di yldioctanoate, 3- (dimethylamino)propyl4-methyl-2,5-bis((9Z,12Z)-octadeca-9,12 -dien-1- yloxy)benzylcarbonate, 3-(((3-(ethyl(methyl)amino)propoxy)carbonyl)oxy)pentadecyl4, 4- bis((2-propylpentyl)oxy)butanoate, 2-(11-dodecyl-3-ethyl-9,15-dioxo-8,10,14-trioxa-3- azanonadecan-19-yl)propane-1,3-diyldioctanoate, 2-(10-dodecyl-3-ethyl-8,15-dioxo-7,9,14- trioxa-3-azanonadecan-19-yl)propane-1,3-diyldioctanoate, 2-(5-((4-((((1-methylpiperidin-4- yl)oxy)carbonyl)oxy)hexadecyl)oxy)-5-oxopentyl)propane-1,3-d iyldioctanoate, 2-(5-((4- ((((1-ethylpiperidin-3-yl)methoxy)carbonyl)oxy)hexadecyl)oxy )-5-oxopentyl)propane-1,3- diyldioctanoate, 2-(5-((4-(((((R)-1-methylpyrrolidin-3-yl)oxy)carbonyl)oxy)he xadecyl)oxy)- 5-oxopentyl)propane-1,3-diyldioctanoate, 2-(5-((4-(((((S)-1-methylpyrrolidin-3- yl)oxy)carbonyl)oxy)hexadecyl)oxy)-5-oxopentyl)propane-1,3-d iyldioctanoate, 2-(5-oxo-5- ((4-(((S)-pyrrolidine-2-carbonyl)oxy)hexadecyl)oxy)pentyl)pr opane-1,3-diyldioctanoate, 2- (5-((4-((1,3-dimethylpyrrolidine-3-carbonyl)oxy)hexadecyl)ox y)-5-oxopentyl)propane-1,3- diyldioctanoate, 2-(5-((4-((1,4-dimethylpiperidine-4-carbonyl)oxy)hexadecyl)o xy)-5- oxopentyl)propane-1,3-diyldioctanoate, 4,4-bis(octyloxy)butyl(3- (diethylamino)propyl)pentadecane-1,3-diyldicarbonate, 3-(((3- (diethylamino)propoxy)carbonyl)oxy)pentadecyl4,4-bis((2-prop ylpentyl)oxy)butanoate, ((2- ((((3-(diethylamino)propoxy)carbonyl)oxy)methyl)-1,4-phenyle ne)bis(oxy))bis(octane-8,1- diyl)bis(decanoate), 4,4-bis(octyloxy)butyl5-(((3- (diethylamino)propoxy)carbonyl)oxy)heptadecanoate, 6-((6,6-bis(octyloxy)hexanoyl)oxy)-4- (((3-(diethylamino)propoxy)carbonyl)oxy)hexyloctanoate, (12Z,15Z)-3-(((3- (diethylamino)propoxy)carbonyl)oxy)henicosa-12,15-dien-1-yl6 ,6-bis(octyloxy)hexanoate, 3- (((3-(diethylamino)propoxy)carbonyl)oxy)tridecyl6,6-bis(octy loxy)hexanoate, 3-(((3- (diethylamino)propoxy)carbonyl)oxy)undecyl6,6-bis(octyloxy)h exanoate, 3-(((3- (diethylamino)propoxy)carbonyl)oxy)pentadecyl5-(4,6-diheptyl -1,3-dioxan-2-yl)pentanoate, 3-((5-(diethylamino)pentanoyl)oxy)pentadecyl6,6-bis(octyloxy )hexanoate, 1-((6,6- bis(octyloxy)hexanoyl)oxy)pentadecan-3-yl1,4-dimethylpiperid ine-4-carboxylate, 3-((3-(1- methylpiperidin-4-yl)propanoyl)oxy)pentadecyl6,6-bis(octylox y)hexanoate, 1-((6,6- bis(octyloxy)hexanoyl)oxy)pentadecan-3-yl1,3-dimethylpyrroli dine-3-carboxylate, 3-(((3- (diethylamino)propoxy)carbonyl)oxy)pentadecyl4,4-bis((2-ethy lhexyl)oxy)butanoate, 2- (((1,3-dimethylpyrrolidine-3-carbonyl)oxy)methyl)propane-1,3 -diylbis(8- (octanoyloxy)octanoate), ((2-((((3-(dimethylamino)propoxy)carbonyl)oxy)methyl)-1,4- phenylene)bis(oxy))bis(octane-8,1-diyl)bis(decanoate), (2R)-1-((6,6- bis(octyloxy)hexanoyl)oxy)pentadecan-3-ylpyrrolidine-2-carbo xylate, (2S)-1-((6,6- bis(octyloxy)hexanoyl)oxy)pentadecan-3-yl1-methylpyrrolidine -2-carboxylate, (2R)-1-((6,6- bis(octyloxy)hexanoyl)oxy)pentadecan-3-yl1-methylpyrrolidine -2-carboxylate, 3-(((3- (dimethylamino)propoxy)carbonyl)oxy)pentadecyl6,6-bis((3-eth ylpentyl)oxy)hexanote, 3- (((3-(dimethylamino)propoxy)carbonyl)oxy)pentadecyl6,6-bis(( 2- propylpentyl)oxy)hexanoate, 3-(((3-(diethylamino)propoxy)carbonyl)oxy)pentadecyl6,6- bis((2-propylpentyl)oxy)hexanoate, 3-(((2- (diethylamino)ethoxy)carbonyl)oxy)pentadecyl6,6-bis(octyloxy )hexanoate, 3-(((3- morpholinoproproxy)carbonyl)oxy)pentadecyl6,6-bis(octyloxy)h exanoate, 3-((((1- methylpiperidin-4-yl)methoxy)carbonyl)oxy)pentadecyl6,6-bis( octyloxy)hexanoate, 3-(((3- (4-methylpiperazin-1-yl)propoxy)carbonyl)oxy)pentadecyl6,6-b is(octyloxy)hexanoate, 3- (((3-(diethylamino)propoxy)carbonyl)oxy)pentadecyl4,4-bis(oc tyloxy)butanoate, 2-(((4- (dimethylamino)butanoyl)oxy)methyl)-2-((dodecanoyloxy)methyl )propane-1,3- diyl(9Z,9'Z)bis-tetradec-9-enoate, (9Z,9'Z,12Z,12'Z)-2-(((4- (dimethylamino)butanoyl)oxy)methyl)propane-1,3-diylbis(octad eca-9,12-dienoate), 3-(((4- (diethylamino)butoxy)carbonyl)oxy)pentadecyl6,6-bis(octyloxy )hexanote, 3-(((3-(piperazin- 1-yl)propoxy)carbonyl)oxy)pentadecyl6,6-bis(octyloxy)hexanoa te, 3-(((3-piperidin-1- yl)propoxy)carbonyl)oxy)pentadecyl6.6-bis(octyloxy)hexanoate , 3-(((3- (dimethylamino)propoxy)carbonyl)oxy)pentadecyl4,4-bis(octylo xy)butanoate, (9Z,9'Z,12Z,12'Z)-2-(9-dodecyl-2-methyl-7,12-dioxo-6,8,13-tr ioxa-2-azatetradecan-14- yl)propane-1,3-diylbis(octadeca-9,12-dienoate), (9Z,12Z)-10-dodecyl-3-ethyl-14-(2- ((9Z,12Z)-octadeca-9,12-dienoyloxy)ethyl)-8,13-dioxo-7,9-dio xa-3,14-diazahexadecan-16- yloctadeca-9,12-dienoate, 2-((2-(((3- (diethylamino)propoxy)carbonyl)oxy)tetradecanoyl)oxy)propane -1,3-diyldioctanoate, 2-(9- dodecyl-2-methyl-7,13-dioxo-6,8,12-trioxa-2-azanonadecan-19- yl)propane-1,3- diyldioctanoate, 2-((decanoyloxy)methyl)-2-(((4- (dimethylamino)butanoyl)oxy)methyl)propane-1,3-diyl(9Z,9'Z)b is-tetradec-9-enoate, (9Z,9'Z,12Z,12'Z)-2-(((3-morpholinopropanoyl)oxy)methyl)prop ane-1,3-diylbis(octadeca- 9,12-dienoate), 3-(Dimethylamino)propylcarbonate(6Z,9Z,28Z,31Z)-heptatricont a-6,9,28,31- tetraen-19-yl, 2,5-bis((9Z,12Z)-octadeca-9,12-dien-1-yloxy)benzyl4- (dimethylamino)butanoate, 2-(10-dodecyl-3-ethyl-8,14-dioxo-7,9,13-trioxa-3-azaoctadeca n- 18-yl)propane-1,3-diyldioctanoate, (9Z,9'Z,12Z,12'Z)-2-(((1,3-dimethylpyrrolidine-3- carbonyl)oxy)methyl)propane-1,3-diylbis(octadeca-9,12-dienoa te), ((5- ((dimethylamino)methyl)benzene-1,2,3-triyl)tris(oxy))tris(de cane10,1-diyl)trioctanoate, 0',0- (((5-((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(prop ane-3,1-diyl))9- dioctyldinonanedioate, (9Z,12Z)-3-(3-((dimethylamino)methyl)-5-(3-((3- octylundecanoyl)oxy)propoxy)phenoxy)propyloctadeca-9,12-dien oate, ((((5- ((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(propane-3 ,1-diyl))bis(oxy))bis(4- oxobutane-4,1-diyl)bis(decanoate), (R)-4-(3-((R)-3,4-bis(octanoyloxy)butoxy)-5- ((dimethylamino)methyl)phenoxy)butane-1,2-diyldioctanoate, (S)-4-(3-((S)-3,4- bis(octanoyloxv)butoxv)-5-((dimethylamino)methyl)phenoxy)but ane-1,2-diyldioctanoate, (R)-4-(3-((S)-3,4-bis(octanoyloxy)butoxy)-5-((dimethylamino) methyl)phenoxy)butane-1,2- diyldioctanoate, 4,4'-((5-((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis( butane1,2- diyl)tetraoctanoate, didodecyl6,6'-((5-((dimethylamino)methyl)-1,3- phenylene)bis(oxy))dihexanoate, di((9Z,12Z)-octadeca-9,12-dien-1-yl)5,5'-((5- ((dimethylamino)methyl)-1,3-phenylene)bis(oxy))dipentanoate, (((5- ((dimethylamino)methyl)-1,3-phenylene)bis(methylene))bis(oxy ))bis(6-oxohexane-6,1- diyl)bis(decanoate), (5-((dimethylamino)methyl)-1,3-phenylene)bis(methylene)bis(8 - (octanoyloxy)octanoate), (5-((dimethylamino)methyl)-1,3-phenylene)bis(methylene)bis(1 0- (octanoyloxy)decanoate), (((5-((dimethylamino)methyl)-1,3- phenylene)bis(methylene))bis(oxy))bis(6-oxohexane-6,1-diyl)d ioctanoate, (((5- ((dimethylamino)methyl)-1,3-phenylene)bis(methylene))bis(oxy ))bis(8-oxooctane-8,1- diyl)bis(decanoate), (9Z,9'Z,12Z,12'Z)-(((5-((dimethylamino)methyl)-1,3- phenylene)bis(methylene))bis(oxy))bis(4-oxobutane-4,1-diyl)b is(octadeca-9,12-dienoate), 0',0-((5-((dimethylamino)methyl)-1,3-phenylene)bis(methylene ))8-dinonyldioctanedioate, 0,0'-((5-((dimethylamino)methyl)-1,3-phenylene)bis(methylene ))bis(10- (octanoyloxy)decyl)disuccinate, 0,0'-((5-((dimethylamino)methyl)-1,3- phenylene)bis(methylene))di((9Z,12Z)-octadeca-9,12-dien-1-yl )disuccinate, (9Z,9'Z,12Z,12'Z)-(5-((((3-(diethylamino)propoxy)carbonyl)ox y)methyl)-1,3- phenylene)bis(methylene)bis(octadeca-9,12-dienoate), (9Z,12Z)-4-(3- ((dimethylarnino)methyl)-5-(4-(oleoyloxy)butoxy)phenoxy)buty loctadeca-9,12-dienoate, (9Z,9'Z,12Z,12'Z,15Z,15'Z)-((5-((dimethvlamino)methyl)-1,3- phenylene)bis(oxy))bis(butane-4,1-diyl)bis(octadeca-9,12,15- trienoate), ((5- ((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(butane-4, 1-diyl)ditetradecanoate, (Z)- ((5-((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(butan e-4,1-diyl)dioleate, ((5- ((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(hexane-6, 1-diyl)didodecanoate, (9Z,9'Z,12Z,12'Z)-((((5-((diethylamino)methyl)-1,3-phenylene )bis(oxy))bis(ethane-2,1- diyl))bis(oxy))bis(ethane-2,1-diyl)bis(octadeca-9,12-dienoat e), didecyl8,8'-((5- ((dimethylamino)methyl)-1,3-phenylene)bis(oxy))dioctanoate, ((5-((dimethylamino)methyl)- 1,3-phenylene)bis(oxy))bis(propane-3,1-diyl)bis(3-octylundec anoate), (9Z.9'Z.12Z.12'Z)-((5- ((diethvlamino)methvn-2-methvl-1.3-phenylene)bis(oxy))bis(bu tane-4,1-diyl)bis(octadeca- 9,12-dienoate), ((5-((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(octan e-8,1- diyl)didodecanoate, ((5-((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(octan e-8,1- diyl)bis(decanoate), (9Z.9'Z.12Z.12'Z)-((5-((dimethvlarnino)methvn-2-methvl-1.3- phenylene)bis(oxy))bis(butane-4,1-diyl)bis(octadeca-9,12-die noate), (8Z,8'Z)-((5- ((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(hexane-bi s(dodec-8-enoate), (9Z,9'Z,12Z,12'Z)-((5-((3-hydroxyazetidin-1-yl)methyl)-1,3-p henylene)bis(oxy))bis(butane- 4,1-diyl)bis(octadeca-9,12-dienoate), ((5-((dimethylamino)methyl)-1,3- phenylene)bis(oxy))bis(hexane-6,1-diyl)dioctanoate, ((5-((dimethylamino)methyl)-1,3- phenylene)bis(oxy))bis(hexane-6,1-diyl)bis(decanoate), (9Z.9'Z.12Z.12'Z)-((5- ((dimethvlamino)methvn-1.3-phenylene)bis(oxy))bis(octane-8,1 -diyl)bis(octadeca-9,12- dienoate), (9Z,9'Z,12Z,12'Z)-((5-((dimethvlamino)methyl)-1,3- phenylene)bis(oxy))bis(hexane-6,1-diyl)bis(octadeca-9,12-die noate), ((5- ((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(decane-10 ,1-diyl)dihexanoate, ((5- ((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(decane-10 ,1-diyl)dioctanoate, ((5- ((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(octane-8, 1-diyl)dioctanoate, ((5- ((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(octane-8, 1-diyl)dihexanoate, (9Z,9'Z,12Z,12'Z)-((5-((dimethvlamino)methyl)-1,3-phenylene) bis(oxy))bis(ethane-2,1- diyl)bis(octadeca-9,12-dienoate), (9Z,9'Z,12Z,12'Z)-((5-((dimethylamino)methyl)-1,3- phenylene)bis(oxy))bis(propane-3,1-diyl)bis(octadeca-9,12-di enoate), (9Z,9'Z,12Z,12'Z)-((5- ((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(butane-4, 1-diyl)bis(octadeca-9,12- dienoate), (5-((dimethylamino)methyl)-1,3-phenylene)bis(methylene)ditri decanoate, (9Z,9'Z,12Z,12'Z)-(5-((dimethylamino)methyl)-1,3-phenylene)b is(methylene)bis(octadeca- 9,12-dienoate), (2,6-bis((9Z,12Z)-octadeca-9,12-dien-1-yloxy)pyridin-4-yl)me thyl3- (dimethylamino)propanoate, (9Z,9'Z,12Z,12'Z)-5-(((3- (dimethylamino)propanoyl)oxy)methyl)-1,3-phenylenebis(octade ca-9,12-dienoate), 1-(3,5- bis((9Z,12Z)-octadeca-9,12-dien-1-yloxy)phenyl)-N,Ndimethylm ethanamine, 3,5- bis((9Z,12Z)-octadeca-9,12-dien-1-yloxy)benzyl3-(dimethylami no)propanoate, 1-(3,5- bis(4,4-bis(octyloxy)butoxy)phenyl)-N,N-dimethylmethanamine, ((((5- ((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(butane-4, 1-diyl))bis(oxy))bis(propane- 3,2,1-triyl)tetraoctanoate, ((5-(((4-(dimethylamino)butanoyl)oxy)methyl)-1,3- phenylene)bis(oxy))bis(octane-8,1-diyl)bis(decanoate), ((5-(((3- (dimethylamino)propanoyl)oxy)methyl)-1,3-phenylene)bis(oxy)) bis(octane-8,1- diyl)bis(decanoate), (9Z,9'Z,12Z,12'Z)-((5-(3-morpholinopropyl)-1,3- phenylene)bis(oxy))bis(butane4,1-diyl)bis(octadeca-9,12-dien oate), (9Z,9'Z,12Z,12'Z)-((5-(3- (dimethvlamino)propyl)-1,3-phenylene)bis(oxy))bis(butane-4,1 -diyl)bis(octadeca-9,12- dienoate), (9Z,9'Z,12Z,12'Z)-((5-(3-(piperidin-1-yl)propyl)-1,3- phenylene)bis(oxy))bis(butane-4,1-diyl)bis(octadeca-9,12-die noate), (5- ((dimethylamino)methyl)-1,3-phenylene)bis(methylene)bis(9-pe ntyltetradecanoate), (5- ((dimethylamino)methyl)-1,3-phenylene)bis(methylene)bis(7-he xyltridecanoate), (5- ((dimethylamino)methyl)-1,3-phenylene)bis(methylene)bis(5-he ptyldodecanoate), ((5- ((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(butane-4, 1-diyl)bis(3- octylundecanoate), ((5-((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(butan e-4,1- diyl)bis(5-heptyldodecanoate), ((5-((dimethylamino)methyl)-1,3- phenylene)bis(oxy))bis(butane-4,1-diyl)bis(9-pentyltetradeca noate), ((5- ((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(butane-4, 1-diyl)bis(7- hexyltridecanoate), (9Z,9'Z,12Z,12'Z)-((5-(pyrrolidin-1-ylmethyl)-1,3- phenylene)bis(oxy))bis(butan4,1-diyl)bis(octadeca-9,12-dieno ate), (((5- ((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(methylene ))bis(propane-3,2,1- triyl)tetraoctanoate, (((5-((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(buta ne-4,1- diyl))bis(propane-3,2,1-triyl)tetraoctanoate, (9Z.12Z)-4-(3-((dimethvlamino)methvn-5-(4-((3- octylundecanoyl)oxy)butoxy)phenoxy)butyloctadeca-9,12-dienoa te, bis(1,3- bis(octanoyloxy)propan-2-yl)0,0'-((5-((dimethylamino)methyl) -1,3- phenylene)bis(methylene))disuccinate, (5-((dimethylamino)methyl)-1,3- phenylene)bis(methylene)bis(6-(((nonyloxy)carbonyl)oxy)hexan oate), 2-(3-(4-(5- ((dimethylamino)methyl)-2-methyl-3-((9Z,12Z)-octadeca9,12-di en-1- yloxy)phenoxy)butoxy)-3-oxopropyl)propane-1,3-diyldihexanoat e, 3- ((dimethylamino)methyl)-5-(((8-(octanoyloxy)octanoyl)oxy)met hyl)benzyl3- octylundecanoate, ((5-((diethylamino)methyl)benzene-1,2,3-triyl)tris(oxy))tris (decane-10,1- diyl)trioctanoate, 1-(3,5-bis((Z)-octadec-9-en-1-yloxy)phenyl)-N,N-dimethylmeth anamine, N'-methyl-N',N".N"-tris((2E.6E)-3.7.11-trimethyldodeca-2.6.1 0-trien-1-vnpropane-1,3- diamine, 1,17-bis(2-((2-pentylcyclopropyl)methyl)cyclopropyl)heptadec an-9-yl4- (dimethylamino)butanoate, ethyl(7Z)-17-{[4-(dimethylamino)butanoyl]oxy}hexacos-7- enoate, (Z)-methyl6-(2-(dimethylamino)-3-(octadec-9-en-1-yloxy)propo xy)hexanoate, 2- (Didodecylamino)-1-(4-(N-(2-(dinonylamino)ethyl)-N-dodecylgl ycyl)piperazin-1-yl)ethan-1- one, 3-((3-(1-(3-((2-(Dinonylamino)ethyl)(nonyl)amino)propanoyl)p iperidin-4- yl)propyl)(nonyl)amino)propylhexanoate, 3-((3-(4-(3-((2- (Dinonylamino)ethyl)(nonyl)amino)propanoyl)piperazin-1-yl)-3 - oxopropyl)(nonyl)amino)propylhexanoate, 3-((2-(Dinonylamino)ethyl)(nonyl)amino)-1-(4- (3-(dinonylamino)propyl)piperidin-1-yl)propan-1-one, Pentyl4-((3-(1-(3-((2- (dinonylamino)ethyl)(nonyl)amino)propanoyl)piperidin-4-yl)pr opyl)(nonyl)amino)butano, Pentyl4-((2-(1-(N-(2-(dinonylamino)ethyl)-N-nonylglycyl)pipe ridin-4- yl)ethyl)(nonyl)amino)butanoate, Pentyl4-(((1-(N-(2-(dinonylamino)ethyl)-N- nonylglycyl)pyrrolidin-3-yl)methyl)(nonyl)amino)butanoate, Pentyl4-((2-(1-(N-(2- (dinonylamino)ethyl)-N-nonylglycyl)pyrrolidin-3-yl)ethyl)(no nyl)amino)butanoate, Pentyl4- ((2-(1-(N-(2-(dinonylamino)ethyl)-N-nonylglycyl)piperidin-3- yl)ethyl)(nonyl)amino)butanoate, 2-(Didodecylamino)-1-(4-(N-(2-(dinonylamino)ethyl)-N- nonylglycyl)piperazin-1-yl)ethan-1-one, 2-((2-(Dinonylamino)ethyl)(nonyl)amino)-1-(3-(2- (dinonylamino)ethyl)piperidin-1-yl)ethan-1-one, Dipentyl4,4'-((2-(4-(N-(2- (dinonylamino)ethyl)-N-nonylglycyl)piperazin-1-yl)-2-oxoethy l)azanediyl)dibutyrate, Pentyl4-(nonyl(2-(4-(N-nonyl-N-(2-(nonyl(4-oxo-4- (pen1yloxy)buryl)amino)ethyl)glycyl)piperazin-1-yl)-2-oxoeth yl)amino)butanoate, 2-((2- (Dinonylamino)ethyl)(nonyl)amino)-1-(3-((dinonylamino)methyl )pyrrolidin-1-yl)ethan-1- one, 2-((2-(Didodecylamino)ethyl)(dodecyl)amino)-1-(4-(dinonylgly cyl)piperazin-1-yl)ethan- 1-one, 2-((2-(Dinonylamino)ethyl)(nonyl)amino)-1-(3-(2-(dinonylamin o)ethyl)pyrrolidin-1- yl)ethan-1-one, Pentyl4-((3-(4-(3-((2- (dinonylamino)ethyl)(nonyl)amino)propanoyl)piperazin-1-yl)-3 - oxopropyl)(nonyl)amino)butanoate, 3-((2-(1-(N-(2-(Dinonylamino)ethyl)-N- nonylglycyl)piperidin-4-yl)ethyl)(nonyl)amino)propylhexanoat e, Butyl5-((2-(1-(N-(2- (dinonylamino)ethyl)-N-nonylglycyl)piperidin-4-yl)ethyl)(non yl)amino)pentanoate, 2-((2- (Didodecylamino)ethyl)(nonyl)amino)-1-(4-(dinonylglycyl)pipe razin-1-yl)ethan-1-one, Propyl6-((2-(1-(N-(2-(dinonylamino)ethyl)-N-nonylglycyl)pipe ridin-4- yl)ethyl)(nonyl)amino)hexanoate, Ethyl7-((2-(1-(N-(2-(dinonylamino)ethyl)-N- nonylglycyl)piperidin-4-yl)ethyl)(nonyl)amino)heptanoate, Methyl8-((2-(1-(N-(2- (dinonylamino)ethyl)-N-nonylglycyl)piperidin-4-yl)ethyl)(non yl)amino)octanoate, 3-((2-(4- (N-(2-(Dinonylamino)ethyl)-N-nonylglycyl)piperazin-1-yl)-2- oxoethyl)(nonyl)amino)propylhexanoate, Butyl5-((2-(4-(N-(2-(dinonylamino)ethyl)-N- nonylglycyl)piperazin-1-yl)-2-oxoethyl)(nonyl)amino)pentanoa te, Propyl6-((2-(4-(N-(2- (dinonylamino)ethyl)-N-nonylglycyl)piperazin-2-oxoethyl)(non yl)amino)hexanoate, Ethyl7- ((2-(4-(N-(2-(dinonylamino)ethyl)-N-nonylglycyl)piperazin-1- yl)-2- oxoethyl)(nonyl)amino)heptanoate, 3-(Dinonylamino)-1-(4-(3-((2- (dinonylamino)ethyl)(nonyl)amino)propanoyl)piperazin-1-yl)pr opan-1-one, 2-((2- (Dinonylamino)ethyl)(nonyl)amino)-1-(4-(ditetradecylglycyl)p iperazin-1-yl)ethan-1-one, 2- (Dinonylamino)-1-(4-(2-((2-(dinonylamino)ethyl)(nonyl)amino) ethyl)piperidin-1-yl)ethan-1- one, 2-(Dinonylamino)-1-(4-(N-(2-(dinonylamino)ethyl)-N-dodecylgl ycyl)piperazin-1- yl)ethan-1-one, 2-((2-(Dinonylamino)ethyl)(nonyl)amino)-1-(4-(2- (dinonylamino)ethyl)piperidin-1-yl)ethan-1-one, Methyl8-((2-(4-(dinonylglycyl)piperazin-1- yl)-2-oxoethyl)(2-((8-methoxy-8-oxooctyl)(nonyl)amino)ethyl) amino)octanoate, Methyl8- ((2-(dinonylamino)ethyl)(2-(4-(dinonylglycyl)piperazin-1-yl) -2-oxoethyl)amino)octanoate, Methyl8-((2-((2-(4-(dinonylglycyl)piperazin-1-yl)-2- oxoethyl)(nonyl)amino)ethyl)(nonyl)amino)octanoate, Pentyl4-((2-(4-(N-(2- (dinonylamino)ethyl)-N-nonylglycyl)piperazin-2-oxoethyl)(non yl)amino)butanoate, Methyl8- ((2-(4-(N-(2-(dinonylamino)ethyl)-N-nonylglycyl)piperazin-1- yl)-2- oxoethyl)(nonyl)amino)octanoate, 2-((2-(Didodecylamino)ethyl)(dodecyl)amino)-1-(5- (dinonylglycyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethan-1-o ne3, 2-(Dinonylamino)-1-(5-(N- (2-(dinonylamino)ethyl)-N-nonylglycyl)-2,5-diazabicyclo[2.2. 1]heptan-2-yl)ethan-1-one, N1,N1,N2-Tri((9Z,12Z)-octadeca-9,12-dien-1-yl)-N2-(2-(pipera zin-1-yl)ethyl)ethane-1,2- diamine, N1,N1,N2-Tri((Z)-octadec-9-en-1-yl)-N2-(2-(piperazin-1-yl)et hyl)ethane-1,2- diamine, 2-(Dinonylamino)-1-(4-(N-(2-(dinonylamino)ethyl)-N-nonylglyc yl)piperazin-1- yl)ethan-1-one, N1,N1,N2-Tridodecyl-N2-(2-(piperazin-1-yl)ethyl)ethane-1,2-d iamine, N1,N1,N2-Trinonyl-N2-(2-(piperazin-1-yl)ethyl)ethane-1,2-dia mine, N1,N1,N2-Trihexyl- N2-(2-(piperazin-1-yl)ethyl)ethane-1,2-diamine, N1-(2-(4-(2- (Didodecylamino)ethyl)piperazin-1-yl)ethyl)-N1,N2,N2-tri((9Z ,12Z)-octadeca-9,12-dien-1- yl)ethane-1,2-diamine, N1-(2-(4-(2-(Didodecylamino)ethyl)piperazin-1-yl)ethyl)-N1,N 2,N2- tri((Z)-octadec-9-en-1-yl)ethane-1,2-diamine, N1-(2-(4-(2- (Ditetradecylamino)ethyl)piperazin-1-yl)ethyl)-N1,N2,N2-trit etradecylethane-1,2-diamine, N1-(2-(4-(2-(Didodecylamino)ethyl)piperazin-1-yl)ethyl)-N1,N 2,N2-tritetradecylethane-1,2- diamine, N1-(2-(4-(2-(Dinonylamino)ethyl)piperazin-1-yl)ethyl)-N1,N2, N2- tritetradecylethane-1,2-diamine, 2-(Didodecylamino)-1-(4-(2-((2- (didodecylamino)ethyl)(dodecyl)amino)ethyl)piperazin-1-yl)et han-1-one, N1-(2-(4-(2- (Di((9Z,12Z)-octadeca-9,12-dien-1-yl)amino)ethyl)piperazin-1 -yl)ethyl)-N1,N2,N2- tridodecylethane-1,2-diamine, N1-(2-(4-(2-(Di((Z)-octadec-9-en-1-yl)amino)ethyl)piperazin- 1-yl)ethyl)-N1,N2,N2-tridodecylethane-1,2-diamine, N1,N1,N2-Tridodecyl-N2-(2-(4-(2- (dodecyl((9Z,12Z)-octadeca-9,12-dien-1-yl)amino)ethyl)pipera zin-1-yl)ethyl)ethane-1,2- diamine, N1-(2-(4-(2-(Ditetradecylamino)ethyl)piperazin-1-yl)ethyl)-N 1,N2,N2- tridodecylethane-1,2-diamine, N1-(2-(4-(2-(Di((Z)-dodec-6-en-1-yl)amino)ethyl)piperazin-1- yl)ethyl)-N1,N2,N^tridodecylethane-1,2-diamine, (Z)-N1-(2-(4-(2-(Dodec-6-en-1- yl(dodecyl)amino)ethyl)piperazin-1-yl)ethyl)-N,N2,N2-tridode cylethane-1,2-diamine, N1-(2- (4-(2-(Dinonylamino)ethyl)piperazin-1-yl)ethyl)-N1,N2,N2-tri dodecylethane-1,2-diamine, N1-(2-(4-(2-(Dioctylamino)ethyl)piperazin-1-yl)ethyl)-N1,N2, N2-tridodecylethane-1,2- diamine, N1-(2-(4-(2-(Dihexylamino)ethyl)piperazin-1-yl)ethyl)-N1,N2, N2-tridodecylethan- 1,2-diamine, N1-(2-(4-(2-(Ditetradecylamino)ethyl)piperazin-1-yl)ethyl)-N 1,N2,N2- trinonylethane-1,2-diamine, 2-((2-(Didodecylamino)ethyl)(dodecyl)amino)-1-(4-(2- (didodecylamino)ethyl)piperazin-1-yl)ethan-1-one, N1-(2-(4-(2- (Didodecylamino)ethyl)piperazin-1-yl)ethyl)-N1,N2,N2-trinony lethane-1,2-diamine, N1-(2- (4-(2-(Dinonylamino)ethyl)piperazin-1-yl)ethyl)-N1,N2,N2-tri nonylethane-1,2-diamine, N1- (2-(4-(2-(Didodecylamino)ethyl)piperazin-1-yl)ethyl)-N1,N2,N 2-trihexylethane-1,2-diamine, Dimethyl12,12'-((2-(4-(2-((2-(didodecylamino)ethyl)(dodecyl) amino)ethyl)piperazin-1- yl)ethyl)azanediyl)didodecanoate, Methyl12-((2-(4-(2-((2- (didodecylamino)ethyl)(dodecyl)amino)ethyl)piperazin-1- yl)ethyl)(dodecyl)amino)dodecanoate, Dipentyl6,6'-((2-(4-(2-((2- (didodecylamino)ethyl)(dodecyl)amino)ethyl)piperazin-1-yl)et hyl)azanediyl)dihexanoate, Pentyl6-((2-(4-(2-((2-(ditetradecylamino)ethyl)(tetradecyl)a mino)ethyl)piperazin-1- yl)ethyl)(dodecyl)amino)hexanoate, Pentyl6-((2-(4-(2-((2- (didodecylamino)ethyl)(dodecyl)amino)ethyl)piperazin-1-yl)et hyl)(dodecyl)amino)hexanoate, 2-(Didodecylamino)-1-(4-(N-(2-(didodecylamino)ethyl)-N-dodec ylglycyl)piperazin-1- yl)ethan-1-one, 2-(Didodecylamino)-1-(4-(N-(2-(didodecylamino)ethyl)-N- nonylglycyl)piperazin-1-yl)ethan-1-one, 2-(Didodecylamino)-N-(2-(4-(2- (didodecylamino)ethyl)piperazin-1-yl)ethyl)-N-dodecylacetami de, ((2-((3,S',4R)-3,4- dihydroxypyrrolidin-1-yl)acetyl)azanediyl)bis(ethane-2,1-diy l)(9Z,9'Z,12Z,12'Z)- bis(octadeca-9,12-dienoate), 2-amino-N,N-dihexadecyl-3-(1H-imidazol-5-yl)propanamide, (2-amino-N,N-dihexadecyl-3-(1H-imidazol-5-yl)propanamide, methyl(9Z)-19-[2- (dimethylamino)ethyl]heptacos-9-enoate, methyl8-(2-{9-[2- (dimethylamino)ethyl]octadecyl}cyclopropyl)octanoate, methyl(9Z)-19-[2- (dimethylamino)ethyl]octacos-9-enoate, ethyl8-(2-{ll- [(dimethylamino)methyl]heptadecyl}cyclopropyl)octanoate, ethyl8-(2-{ll- [(dimethylamino)methyl]octadecyl}cyclopropyl)octanoate, di((9Z,12Z)-octadeca-9,12-dien-1- yl)3-(((2-(dimethylamino)ethoxy)carbonyl)amino)pentanedioate , Heptyl6-((2-(l-(N-(2- (dinonylamino)ethyl)-N-nonylglycyl)piperidin-4-yl)ethyl)(tet radecyl)amino)hexanoate, ethyl8-(2-{ll-[(dimethylamino)methyl]nonadecyl}cyclopropyl)o ctanoate, Pentyl8-((2-(l-(N- (2-(dinonylamino)ethyl)-N-nonylglycyl)piperidin-4-yl)ethyl)( tetradecyl)amino)octanoate, ethyl8-(2-{ll-[(dimethylamino)methyl]icosyl}cyclopropyl)octa noate, ethyl8-(2-{9- [(dimethylamino)methyl]pentadecyl}cyclopropyl)octanoate, 3-((2-(l-(N-(2- (Dinonylamino)ethyl)-N-nonylglycyl)piperidin-4- yl)ethyl)(tetradecyl)amino)propyldecanoate, Heptyl6-((2-(4-(N-(2-(dinonylamino)ethyl)-N- nonylglycyl)piperazin-1-yl)-2-oxoethyl)(tetradecyl)amino)hex anoate, ethyl8-(2-{9- [(dimethylamino)methyl]hexadecyl}cyclopropyl)octanoate, Pentyl8-((2-(4-(N-(2- (dinonylamino)ethyl)-N-nonylglycyl)piperazin-2-oxoethyl)(tet radecyl)amino)octanoate, ethyl8-(2-{9-[(dimethylamino)methyl]heptadecyl}cyclopropyl)o ctanoate, methyl6-(2-(8-(2- (dimethylamino)-3-(nonyloxy)propoxy)octyl)cyclopropyl)hexano ate, methyl(9Z)-21- (dimethylamino)heptacos-9-enoate, methyl(9Z)-21-{[4- (dimethylamino)butanoyl]oxy}heptacos-9-enoate, (2R)-N,N-dimethyl-1-[(9Z,12Z)-octadeca- 9,12-dien-1-yloxy]dodecan-2-amine, (15Ζ,18Ζ)-Ν,Ν-dimethyltetracoda-15,18-dien-5-amine, ethyl8-(2-{9-[(dimethylamino)methyl]octadecyl}cyclopropyl)oc tanoate, 3-((2-(4-(N-(2- (Dinonylamino)ethyl)-N-nonylglycyl)piperazin-1-yl)-2- oxoethyl)(tetradecyl)amino)propyldecanoate, ethyl4-(2-{ll- [(dimethylamino)methyl]icosyl}cyclopropyl)butanoate, ethyl8-(2-{7- [(dimethylamino)methyl]hexadecyl}cyclopropyl)octanoate, 3-((3-(1-(3-((2- (Dinonylamino)ethyl)(nonyl)amino)propanoyl)piperidin-4- yl)propyl)(nonyl)amino)propylhexanoate, ethyl6-(2-{9- [(dimethylamino)methyl]pentadecyl}cyclopropyl)hexanoate, 3-((3-(4-(3-((2- (Dinonylamino)ethyl)(nonyl)amino)propanoyl)piperazin-1-yl)-3 - oxopropyl)(nonyl)amino)propylhexanoate, ethyl6-(2-{9- [(dimethylamino)methyl]hexadecyl}cyclopropyl)hexanoate, 3-((2- (Dinonylamino)ethyl)(nonyl)amino)-1-(4-(3-(dinonylamino)prop yl)piperidin-1-yl)propan-1- one, Pentyl4-((3-(l-(3-((2-(dinonylamino)ethyl)(nonyl)amino)propa noyl)piperidin-4- yl)propyl)(nonyl)amino)buta^, ethyl6-(2-{9- [(dimethylamino)methyl]heptadecyl}cyclopropyl)hexanoate, Pentyl4-((2-(1-(N-(2- (dinonylamino)ethyl)-N-nonylglycyl)piperidin-4-yl)ethyl)(non yl)amino)butanoate, ethyl6-(2- {9-[(dimethylamino)methyl]octadecyl}cyclopropyl)hexanoate, Pentyl4-(((1-(N-(2- (dinonylamino)ethyl)-N-nonylglycyl)pyrrolidin-3-yl)methyl)(n onyl)amino)butanoate, ethyl(9Z)-21-[(dimethylamino)methyl]heptacos-9-enoate, Pentyl4-((2-(1-(N-(2- (dinonylamino)ethyl)-N-nonylglycyl)pyrrolidin-3-yl)ethyl)(no nyl)amino)butanoate, ethyl(9Z)-21-[(dimethylamino)methyl]octacos-9-enoate, ((2-((3,S',4R)-3,4- dihydroxypyrrolidin-1-yl)acetyl)azanediyl)bis(ethane-2,1-diy l)(9Z,9'Z,12Z,12'Z)- bis(octadeca-9,12-dienoate), Pentyl4-((2-(1-(N-(2-(dinonylamino)ethyl)-N- nonylglycyl)piperidin-3-yl)ethyl)(nonyl)amino)butanoate, ethyl(9Z)-21- [(dimethylamino)methyl]nonacos-9-enoate, methyl6-(2-(8-(2-(dimethylamino)-3- (heptyloxy)propoxy)octyl)cyclopropyl)hexanoate, methyl(9Z)-21-{[4- (dimethylamino)butanoyl]oxy}octacos-9-enoate, methyl(9Z)-21-(dimethylamino)octacos-9- enoate, 2-(Didodecylamino)-1-(4-(N-(2-(dinonylamino)ethyl)-N-nonylgl ycyl)piperazin-1- yl)ethan-1-, (2S)-N.N-dimethyl-1-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]non an-2-amine, (18Z,21Z)-N,N-dimethylheptacosa-18,21-dien-10-amine, ethyl(9Z)-21- [(dimethylamino)methyl]triacont-9-enoate, ethyl(9Z)-19-[(dimethylamino)methyl]pentacos- 9-enoate, ethyl(9Z)-19-[(dimethylamino)methyl]hexacos-9-enoate, ethyl(9Z)-19- [(dimethylamino)methyl]heptacos-9-enoate, ethyl(9Z)-19-[(dimethylamino)methyl]octacos- 9-enoate, ethyl(5Z)-17-[(dimethylamino)methyl]hexacos-5-enoate, ethyl(9Z)-17- [(dimethylamino)methyl]hexacos-9-enoate, 2-((2-(Dinonylamino)ethyl)(nonyl)amino)-1-(3- (2-(dinonylamino)ethyl)piperidin-1-yl)ethan-1-one, ethyl(7Z)-17- [(dimethylamino)methyl]tricos-7-enoate, Dipentyl4,4'-((2-(4-(N-(2-(dinonylarnino)ethyl)-N- nonylglycyl)piperazin-1-yl)-2-oxoethyl)azanediyl)dibutyrate, Pentyl4-(nonyl(2-(4-(N-nonyl- N-(2-(nonyl(4-oxo-4-(pentyloxy)butyl)amino)ethyl)glycyl)pipe razin-1-yl)-2- oxoethyl)amino)butanoate, ethyl(7Z)-17-[(dimethylamino)methyl]tetracos-7-enoate, ethyl(7Z)-17-[(dimethylamino)methyl]pentacos-7-enoate, 2-((2- (Dinonylamino)ethyl)(nonyl)amino)-1-(3-((dinonylamino)methyl )pyrrolidin-1-yl)ethan-1- one, trans-3-[(3}7-dimethyloctyl)oxy]-1-methyl-4~[(9Z,12Z)-octade ca-9512-dien-1- yloxyjpyrrolidine, methyl6-(2-(8-(2-(dimethylamino)-3- (hexyloxy)propoxy)octyl)cyclopropyl)hexanoate, methyl(9Z)-21-{[4- (dimethylamino)butanoyl]oxy}nonacos-9-enoate, methyl(9Z)-21-(dimethylamino)nonacos-9- enoate, (2S)-N,N-dimethyl-1-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]tri decan-2-amine, (15Z,18Z)-N,N-dimethyltetracosa-15,18-dien-7-amine, ethyl(7Z)-17- [(dimethylamino)methyl]hexacos-7-enoate, 2-((2-(Dinonylamino)ethyl)(nonyl)amino)-1-(3- (2-(dinonylamino)ethyl)pyrrolidin-1-yl)ethan-1-one, methyl6-(2-{ll- [(dimethylamino)methyl]icosyl}cyclopropyl)hexanoate, methyl10-(2-{7- [(dimethylamino)methyl]hexadecyl}cyclopropyl)decanoate, methyl8-(2-{ll- [(dimethylamino)methyl]heptadecyl}cyclopropyl)octanoate, methyl8-(2-{ll- [(dimethylamino)methyl]octadecyl}cyclopropyl)octanoate, methyl8-(2-{ll- [(dimethylamino)methyl]nonadecyl}cyclopropyl)octanoate, methyl8-(2-{ll- [(dimethylamino)methyl]icosyl}cyclopropyl)octanoate, Pentyl4-((3-(4-(3-((2- (dinonylamino)ethyl)(nonyl)amino)propanoyl)piperazin-1-yl)-3 - oxopropyl)(nonyl)amino)butanoate, methyl8-(2-{9- [(dimethylamino)methyl]pentadecyl}cyclopropyl)octanoate, methyl8-(2-{9- [(dimethylamino)methyl]hexadecyl}cyclopropyl)octanoate, 3-((2-(l-(N-(2- (Dinonylamino)ethyl)-N-nonylglycyl)piperidin-4-yl)ethyl)(non yl)amino)propylhexanoate, methyl8-(2-{9-[(dimethylamino)methyl]heptadecyl}cyclopropyl) octanoate, methyl8-(2- (dimethylamino)-3-((6-((2-octylcyclopropyl)methoxy)-6-oxohex yl)oxy)propoxy)octanoate, Butyl5-((2-(1-(N-(2-(dinonylamino)ethyl)-N-nonylglycyl)piper idin-4- yl)ethyl)(nonyl)amino)pentanoate, trans-1-methyl-3-[(12Z)-octadec-12-en-1-yloxy]-4- (octyloxy)pyrrolidine, methyl(9Z)-21-{[4-(dimethylamino)butanoyl]oxy}triacont-9-eno ate, methyl(9Z)-21-(dimethylamino)triacont-9-enoate, 2-((2- (Didodecylamino)ethyl)(nonyl)amino)-1-(4-(dinonylglycyl)pipe razin-1-yl)ethan-1- oneStep1:MethylN-(2-(didodecylamino)ethyl)-N-nonylglycinate, 1-((2R,3S,5R)-3- (bis(hexadecyloxy)methoxy)-5-(5-methyl-2,4-dioxo-3,4-dihydro pyrimidin-1(2H)- yl)tetrahydrofumethanesulfonate, (Z)-methyl16-(3-(decyloxy)-2- (dimethylamino)propoxy)hexadec-7-enoate, (2S)-1-[(9Z,12Z)-octadeca-9,12-dien-1- yloxy]nonan-2-amine, (14Z,17Z)-N,N-dimethyltricosa-14,17-dien-6-amine, Propyl6-((2-(1- (N-(2-(dinonylamino)ethyl)-N-nonylglycyl)piperidin-4-yl)ethy l)(nonyl)amino)hexanoate, methyl7-(2-(dimethylamino)-3-((6-((2-octylcyclopropyl)methox y)-6- oxohexyl)oxy)propoxy)heptanoate, methyl(7Z)-19-[(dimethylamino)methyl]octacos-7- enoate, methyl(HZ)-19-[(dimethylamino)methyl]octacos-ll-enoate, Ethyl7-((2-(l-(N-(2- (dinonylamino)ethyl)-N-nonylglycyl)piperidin-4-yl)ethyl)(non yl)amino)heptanoate, (2- octylcyclopropyl)methyl6-(2-(dimethylamino)-3-((5-methoxy-5- oxopentyl)oxy)propoxy)hexanoate, Methyl8-((2-(l-(N-(2-(dinonylamino)ethyl)-N- nonylglycyl)piperidin-4-yl)ethyl)(nonyl)amino)octanoate, methyl(9Z)-21- [(dimethylamino)methyl]heptacos-9-enoate, (2-octylcyclopropyl)methyl6-(2- (dimethylamino)-3-(4-methoxy-4-oxobutoxy)propoxy)hexanoate, methyl(9Z)-21- [(dimethylamino)methyl]octacos-9-enoate, 3-((2-(4-(N-(2-(Dinonylamino)ethyl)-N- nonylglycyl)piperazin-1-yl)-2-oxoethyl)(nonyl)amino)propylhe xanoate, (Z)-methyl8-(2- (dimethylamino)-3-((6-oxo-6-(undec-2-en-1-yloxy)hexyl)oxy)pr opoxy)octanoate, methyl(9Z)-21-[(dimethylamino)methyl]nonacos-9-enoate, Butyl5-((2-(4-(N-(2- (dinonylamino)ethyl)-N-nonylglycyl)piperazin-1-yl)-2-oxoethy l)(nonyl)amino)pentanoate, (Z)-methyl7-(2-(dimethylamino)-3-((6-oxo-6-(undec-2-en-1- yloxy)hexyl)oxy)propoxy)heptanoate, Propyl6-((2-(4-(N-(2-(dinonylamino)ethyl)-N- nonylglycyl)piperazin-1-yl)-2-oxoethyl)(nonyl)amino)hexanoat e, methyl(9Z)-21- [(dimethylamino)methyl]triacont-9-enoate, (Z)-undec-2-en-1-yl6-(2-(dimethylamino)-3-((5- methoxy-5-oxopentyl)oxy)propoxy)hexanoate, methyl(9Z)-19- [(dimethylamino)methyl]pentacos-9-enoate, Ethyl7-((2-(4-(N-(2-(dinonylamino)ethyl)-N- nonylglycyl)piperazin-1-yl)-2-oxoethyl)(nonyl)amino)heptanoa te, (Z)-undec-2-en-1-yl6-(2- (dimethylamino)-3-(4-methoxy-4-oxobutoxy)propoxy)hexanoate, methyl6-(2- (dimethylamino)-3-((6-((2-octylcyclopropyl)methoxy)-6-oxohex yl)oxy)propoxy)hexanoate, methyl(9Z)-19-[(dimethylamino)methyl]hexacos-9-enoate, 3-(Dinonylamino)-1-(4-(3-((2- (dinonylamino)ethyl)(nonyl)amino)propanoyl)piperazin-1-yl)pr opan-1-one, methyl(9Z)-19- [(dimethylamino)methyl]heptacos-9-enoate, 2-((2-(Dinonylamino)ethyl)(nonyl)amino)-1-(4- (ditetradecylglycyl)piperazin-1-yl)ethan-1-one, (Z)-methyl6-(2-(dimethylamino)-3-((6-oxo-6- (undec-2-en-1-yloxy)hexyl)oxy)propoxy)hexanoate, methyl8-(2-(dimethylamino)-3-((8-(2-(6- methoxy-6-oxohexyl)cyclopropyl)octyl)oxy)propoxy)octanoate, methyl8-(2-{9- [(dimethylamino)methyl]octadecyl}cyclopropyl)octanoate, 2-(Dinonylamino)-1-(4-(2-((2- (dinonylamino)ethyl)(nonyl)amino)ethyl)piperidin-1-yl)ethan- 1-one, trans-1-methyl-3-[(9Z)- octadec-9-en-1-yloxy]-4-(octyloxy)pyrrolidine, methyl(9Z)-19-{[4- (dimethylamino)butanoyl]oxy}pentacos-9-enoate, methyl(9Z)-19-(dimethylamino)pentacos- 9-enoate, (Z)-methyl16-(2-(dimethylamino)-3-(nonyloxy)propoxy)hexadec- 7-enoate, (2S)-1- [(9Z,12Z)-octadeca-9,12-dien-1-yloxy]decan-2-amine, (12Z,15Z)-N,N-dimethylhenicosa- 12,15-dien-4-amine, methyl7-(2-(dimethylamino)-3-((8-(2-(6-methoxy-6- oxohexyl)cyclopropyl)octyl)oxy)propoxy)heptanoate, methyl(9Z)-19- [(dimethylamino)methyl]octacos-9-enoate, 2-((2-(Dinonylamino)ethyl)(nonyl)amino)-1-(4-(2- (dinonylamino)ethyl)piperidin-1-yl)ethan-1-one, Methyl8-((2-(4-(dinonylglycyl)piperazin-1- yl)-2-oxoethyl)(2-((8-methoxy-8-oxooctyl)(nonyl)amino)ethyl) amino)octanoate, methyl6-(2- (8-(2-(dimethylamino)-3-((5-methoxy-5- oxopentyl)oxy)propoxy)octyl)cyclopropyl)hexanoate, ethyl8-{2-[ll- (dimethylamino)heptadecyl]cyclopropyl}octanoate, Methyl8-((2-(dinonylamino)ethyl)(2-(4- (dinonylglycyl)piperazin-1-yl)-2-oxoethyl)amino)octanoate, methyl6-(2-(8-(2- (dimethylamino)-3-(4-methoxy-4-oxobutoxy)propoxy)octyl)cyclo propyl)hexanoate, ethyl8- {2-[ll-(dimethylamino)octadecyl]cyclopropyl}octanoate, Methyl8-((2-((2-(4- (dinonylglycyl)piperazin-1-yl)-2-oxoethyl)(nonyl)amino)ethyl )(nonyl)amino)octanoate, ethyl8-{2-[ll-(dimethylamino)nonadecyl]cyclopropyl}octanoate , (Z)-methyl16-(2- (dimethylamino)-3-((8-methoxy-8-oxooctyl)oxy)propoxy)hexadec -7-enoate, Pentyl4-((2-(4- (N-(2-(dinonylamino)ethyl)-N-nonylglycyl)piperazin-1-yl)-2- oxoethyl)(nonyl)amino)butanoate, ethyl8-{2-[ll- (dimethylamino)icosyl]cyclopropyl}octanoate, (Z)-methyl16-(2-(dimethylamino)-3-((7- methoxy-7-oxoheptyl)oxy)propoxy)hexadec-7-enoate, Methyl8-((2-(4-(N-(2- (dinonylamino)ethyl)-N-nonylglycyl)piperazin-1-yl)-2-oxoethy l)(nonyl)amino)octanoate, ethyl8-{2-[9-(dimethylamino)pentadecyl]cyclopropyl}octanoate , (Z)-methyl16-(2- (dimethylamino)-3-((5-methoxy-5-oxopentyl)oxy)propoxy)hexade c-7-enoate, (11E,20Z,23Z)-N,N-dimethylnonacosa-11,20,23-trien-10-amine, N,N-dimethyl-1-[(1S,2R)-2- octylcyclopropyl]pentadecan-8-amine, ethyl8-{2-[9- (dimethylamino)hexadecyl]cyclopropyl}octanoate, 2-((2- (Didodecylamino)ethyl)(dodecyl)amino)-1-(5-(dinonylglycyl)-2 ,5-diazabicyclo[2.2.1]heptan- 2-yl)ethan-1-one3, (Z)-methyl16-(2-(dimethylamino)-3-(4-methoxy-4- oxobutoxy)propoxy)hexadec-7-enoate, methyl6-(2-(8-(2-(dimethylamino)-3-((6-methoxy-6- oxohexyl)oxy)propoxy)octyl)cyclopropyl)hexanoate, ethyl8-{2-[9- (dimethylamino)heptadecyl]cyclopropyl}octanoate, 2-(Dinonylamino)-1-(5-(N-(2- (dinonylamino)ethyl)-N-nonylglycyl)-2,5-diazabicyclo[2.2.1]h eptan-2-yl)ethan-1-one, 1- [(1S,2R)-2-decylcyclopropyl]-N,N-dimethylpentadecan-6-amine, N1,N1,N2-Tri((9Z,12Z)- octadeca-9,12-dien-1-yl)-N2-(2-(piperazin-1-yl)ethyl)ethane- 1,2-diamine, ethyl8-{2-[9- (dimethylamino)octadecyl]cyclopropyl}octanoate, 1-[(1R,2S)-2-heptylcyclopropyl]-Ν,Ν- dimethyloctadecan-9-amine, (Z)-methyl16-(2-(dimethylamino)-3-((6-methoxy-6- oxohexyl)oxy)propoxy)hexadec-7-enoate, N1,N1,N2-Tri((Z)-octadec-9-en-1-yl)-N2-(2- (piperazin-1-yl)ethyl)ethane-1,2-diamine, N,N-dimethyl-3-{7-[(1S,2R)-2- octylcyclopropyl]heptyl}dodecan-1-amine, methyl8-(2-(dimethylamino)-3-((8-(2-((2- pentylcyclopropyl)methyl)cyclopropyl)octyl)oxy)propoxy)octan oate, ethyl4-{2-[ll- (dimethylamino)icosyl]cyclopropyl}butanoate, trans-1-Methyl-3-[((9Z,12Z)-octadeca-9,12- dienyl)oxy]-4-octyloxy-pyrrolidine, methyl(9Z)-19-(dimethylamino)hexacos-9-enoate, methyl(9Z)-19-{[4-(dimethylamino)butanoyl]oxy}hexacos-9-enoa te, (Z)-methyl16-(2- (dimethylamino)-3-(heptyloxy)propoxy)hexadec-7-enoate, (2R)-1-[(9Z,12Z)-octadeca-9,12- dien-1-yloxy]dodecan-2-amine, (13Z,16Z)-N,N-dimethyldocosa-13,16-dien-5-amine, Ν,Ν- dimethyl-1-[(1R,2S)-2-undecylcyclopropyl]tetradecan-5-amine, methyl7-(2- (dimethylamino)-3-((8-(2-((2- pentylcyclopropyl)methyl)cyclopropyl)octyl)oxy)propoxy)hepta noate, ethyl8-{2-[7- (dimethylamino)hexadecyl]cyclopropyl}octanoate, 2-(Didodecylamino)-N-dodecyl-N-(2- (piperazin-1-yl)ethyl)acetamide, Ν,Ν-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]hexadecan-8- amine, N1-(2-(Piperazin-1-yl)ethyl)-N1,N2,N2-tritetradecylethane-1, 2-diamine, methyl6-(2- (dimethylamino)-3-((8-(2-((2- pentylcyclopropyl)methyl)cyclopropyl)octyl)oxy)propoxy)hexan oate, ethyl6-{2-[9- (dimethylamino)pentadecyl]cyclopropyl}hexanoate, Ν,Ν-dimethyl-1-[(1S,2S)-2-{[(1R,2R)- 2-pentylcyclopropyl]methyl}cyclopropyl]nonadecan-10-amine, NN1,N2-Tridodecyl-N2-(2- (piperazin-1-yl)ethyl)ethane-1,2-diamine, methyl5-(2-(dimethylamino)-3-((8-(2-((2- pentylcyclopropyl)methyl)cyclopropyl)octyl)oxy)propoxy)penta noate, ethyl6-{2-[9- (dimethylamino)hexadecyl]cyclopropyl}hexanoate, N,N-dimethyl-21-[(1S,2R)-2- octylcyclopropyl]henicosan-10-amine, NNN2-Trinonyl-N2-(2-(piperazin-1-yl)ethyl)ethane- 1,2-diamine, methyl4-(2-(dimethylamino)-3-((8-(2-((2- pentylcyclopropyl)methyl)cyclopropyl)octyl)oxy)propoxy)butan oate, ethyl6-{2-[9- (dimethylamino)heptadecyl]cyclopropyl}hexanoate, Ν,Ν-dimethyl-1-[(1S,2R)-2- octylcyclopropyl]nonadecan-10-amine, N1,N1,N2-Trihexyl-N2-(2-(piperazin-1- yl)ethyl)ethane-1,2-diamine, methyl8-(2-(dimethylamino)-3-((9Z,12Z)-octadeca-9,12-dien-1- yloxy)propoxy)octanoate, ethyl6-{2-[9-(dimethylamino)octadecyl]cyclopropyl}hexanoate, N1-(2-(4-(2-(Didodecylamino)ethyl)piperazin-1-yl)ethyl)-N1,N 2,N2-tri((9Z,12Z)-octadeca- 9,12-dien-1-yl)ethane-1,2-diamine, methyl7-(2-(dimethylamino)-3-((9Z,12Z)-octadeca-9,12- dien-1-yloxy)propoxy)heptanoate, ethyl(9Z)-21-(dimethylamino)heptacos-9-enoate, 1- [(1S,2R)-2-hexylcyclopropyl]-N,N-dimethylnonadecan-10-amine, 1-methyl18-[(2Z)-non-2- en-1-yl]9-{[4-(dimethylamino)butanoyl]oxy}octadecanedioate, N1-(2-(4-(2- (Didodecylamino)ethyl)piperazin-1-yl)ethyl)-N1,N2,N2-tri((Z) -octadec-9-en-1-yl)ethane-1,2- diamine, N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]heptadecan-8-amin e, methyl6-(2- (dimethylamino)-3-((9Z,12Z)-octadeca-9,12-dien-1-yloxy)propo xy)hexanoate, ethyl(9Z)-21- (dimethylamino)octacos-9-enoate, dimethyl(9Z)-19-{[4- (dimethylamino)butanoyl]oxy}heptacos-9-enedioate, N1-(2-(4-(2- (Ditetradecylamino)ethyl)piperazin-1-yl)ethyl)-N1,N2,N2-trit etradecylethane-1,2-diamine, methyl5-(2-(dimethylamino)-3-((9Z,12Z)-octadeca-9,l2-dien-1- yloxy)propoxy)pentanoate, ethyl8-{[4-(dimethylamino)butanoyl]oxy}-15-(2-octylcycloprop yl)pentadecanoate, ethyl(9Z)-21-(dimethylamino)nonacos-9-enoate, (13Z,16Z)-N,N-dimethyl-3-nonyldocosa- 13,16-dien-1-amine, N1-(2-(4-(2-(Didodecylamino)ethyl)piperazin-1-yl)ethyl)-N1,N 2,N2- tritetradecylethane-1,2-diamine, methyl9-{[4-(dimethylamino)butanoyl]oxy}-16-(2- octylcyclopropyl)hexadecanoate, methyl4-(2-(dimethylamino)-3-((9Z,12Z)-octadeca-9,12- dien-1-yloxy)propoxy)butanoate, ethyl(9Z)-21-(dimethylamino)triacont-9-enoate, (12Z,15Z)- N,N-dimethyl-2-nonylhenicosa-12,15-dien-1-amine, methyl8-(2-(dimethylamino)-3-((8-(2- octylcyclopropyl)octyl)oxy)propoxy)octanoate, ethyl(9Z)-19-(dimethylamino)pentacos-9- enoate, ethyl(18Z,21Z)-8-{[4-(dimethylamino)butanoyl]oxy}heptacosa-1 8,21-dienoate, (16Z)-N,N-dimethylpentacos-16-en-8-amine, methyl(9Z)-19-{[4- (dimethylamino)butanoyl]oxy}heptacos-9-enoate, methyl(9Z)-19-(dimethylamino)heptacos- 9-enoate, 2-(Didodecylamino)-1-(4-(2-((2- (didodecylamino)ethyl)(dodecyl)amino)ethyl)piperazin-1-yl)et han-1-one, (Z)-methyl16-(2- (dimethylamino)-3-(hexyloxy)propoxy)hexadec-7-enoate, (2S)-1-[(9Z,12Z)-octadeca-9,12- dien-1-yloxy]dodecan-2-amine, (16Z,19Z)-N,N-dimethylpentacosa~16,19-dien-8-amine, N1- (2-(4-(2-(Dinonylamino)ethyl)piperazin-1-yl)ethyl)-N1,N2^V2- tritetradecylethane-1,2- diamine, methyl7-(2-(dimethylamino)-3-((8-(2- octylcyclopropyl)octyl)oxy)propoxy)heptanoate, methyl(19Z,22Z)-9-{[4- (dimethylamino)butanoyl]oxy}octacosa-19,22-dienoate, ethyl(9Z)-19- (dimethylamino)hexacos-9-enoate, (22Z)-N,N-dimethylhentriacont-22-en-10-amine, N1-(2- (4-(2-(Di((Z)-octadec-9-en-1-yl)amino)ethyl)piperazin-1-yl)e thyl)- !^^-tridodecylethane-1,2- diamine, methyl5-(2-(dimethylamino)-3-((8-(2- octylcyclopropyl)octyl)oxy)propoxy)pentanoate, ethyl(9Z)-19-(dimethylamino)heptacos-9- enoate, (2-butylcyclopropyl)methyl12-{[4-(dimethylamino)butanoyl]oxy }henicosanoate, (20Z)-N,N-dimethylnonacos-20-en-10-amine, N1,N1,N2-Tridodecyl-N2-(2-(4-(2- (dodecyl((9Z,12Z)-octadeca-9,12-dien--yl)amino)ethyl)piperaz in-1-yl)ethyl)ethane-1,2- diamine, methyl4-(2-(dimethylamino)-3-((8-(2- octylcyclopropyl)octyl)oxy)propoxy)butanoate, ethyl(9Z)-19-(dimethylamino)octacos-9- enoate, (2-octylcyclopropyl)methyl8-{[4-(dimethylamino)butanoyl]oxy} heptadecanoate, (24Z)-N,N-dimethyltritriacont-24-en-10-amine, N1-(2-(4-(2- (Ditetradecylamino)ethyl)piperazin-1-yl)ethyl)-N1,N2,N2-trid odecylethane-1,2-diamine, ethyl(5Z)-17-(dimethylamino)hexacos-5-enoate, (Z)-methyl8-(2-(dimethylamino)-3-(octadec- 9-en-1-yloxy)propoxy)octanoate, (2Z)-hept-2-en-1-yl12-{[4- (dimethylamino)butanoyl]oxy}henicosanoate, (17Z)-N,N-dimethylnonacos-17-en-10-amine, N1-(2-(4-(2-(Di((Z)-dodec-6-en-1-yl)amino)ethyl)piperazin-1- yl)ethyl)-N1,N2,N2- tridodecylethane-1,2,-diamine, ethyl(9Z)-17-(dimethylamino)hexacos-9-enoate, (Z)-methyl7- (2-(dimethylamino)-3-(octadec-9-en-1-yloxy)propoxy)heptanoat e, (2Z)-undec-2-en-1-yl8-{[4- (dimethylamino)butanoyl]oxy}heptadecanoate, (14Z)-N,N-dimethylnonacos-14-en-10-amine, ethyl(7Z)-17-(dimethylamino)tricos-7-enoate, (Z)-N1-(2-(4-(2-(Dodec-6-en-1- yl(dodecyl)amino)ethyl)piperazin-N!^^-tridodecylethane-1,2-d iamine, (Z)-methyl5-(2- (dimethylamino)-3-(octadec-9-en-1-yloxy)propoxy)pentanoate, (2- hexylcyclopropyl)methyl10-{[4-(dimethylamino)butanoyl]oxy}no nadecanoate, (15Z)-N,N- dimethylheptacos-15-en-10-amine, ethyl(7Z)-17-(dimethylamino)tetracos-7-enoate, (Z)- methyl4-(2-(dimethylamino)-3-(octadec-9-en-1-yloxy)propoxy)b utanoate, (2Z)-non-2-en-1- yl10-{[4-(dimethylamino)butanoyl]oxy}nonadecanoate, (20Z)-N,N-dimethylheptacos-20-en- 10-amine, N1-(2-(4-(2-(Dioctylamino)ethyl)piperazin-1-yl)ethyl)-N1,N2^ V2- tridodecylethane-1,2-diamine, methyl6-(2-(dimethylamino)-3-((8-(2- octylcyclopropyl)octyl)oxy)propoxy)hexanoate, ethyl6-[2-(9-{[4- (dimethylamino)butanoyl]oxy}octadecyl)cyclopropyl]hexanoate, ethyl(7Z)-17- (dimethylamino)pentacos-7-enoate, 1-[(11Z,14Z)-1-nonylicosa-11,14-dien-1-yl]pyrrolidine, ethyl(7Z)-17-(dimethylamino)hexacos-7-enoate, (20Z,23Z)-N-ethyl-N-methylnonacosa- 20,23-dien-10-amine, N,N-dimethylheptacosan-10-amine, methyl6-{2-[ll- (dimethylamino)icosyl]cyclopropyl}hexanoate, methyl6-[2-(ll-{[4- (dimethylamino)butanoyl]oxy}icosyl)cyclopropyl]hexanoate, (2-octylcyclopropyl)methyl6- (3-(decyloxy)-2-(dimethylamino)propoxy)hexanoate, methyl8-{2-[9- (dimethylamino)octadecyl]cyclopropyl}octanoate, methyl8-[2-(9-{[4- (dimethylamino)butanoyl]oxy}octadecyl)cyclopropyl]octanoate, methyl7-(2-(8-(2- (dimethylamino)-3-(octyloxy)propoxy)octyl)cyclopropyl)heptan oate, Heptadecan-9-yl8-((2- hydroxyethyl)(tetradecyl)amino)octanoateRepresentative, 2-((2- (Didodecylamino)ethyl)(dodecyl)amino)-1-(4-(2-(didodecylamin o)ethyl)piperazin-1-yl)ethan- 1-one, (2S)-1-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]undecan-2-amine, (17Z,20Z)-N,N- dimemylhexacosa-17,20-dien-9-amine, (18Z)-heptacos-18-en-10-yl4- (dimethylamino)butanoate, (2S)-1-({6-[3B))-cholest-5-en-3-yloxy]hexyl}oxy)-N,N-dimethy l- 3-[(9Z)-octadec-9-en-1-yloxy]propan-2-amine, methyl10-{2-[7- (dimethylamino)hexadecyl]cyclopropyl}decanoate, methyl10-[2-(7-{[4- (dimethylamino)butanoyl]oxy}hexadecyl)cyclopropyl]decanoate, (2S)-N,N-dimethyl-1-({8- [(lR,2R)-2-{[(lS,2S)-2-pentylcyclopropyl]methyl}cyclopropyl] octyl}oxy)tridecan-2-amine, (2-octylcyclopropyl)methyl6-(2-(dimethylamino)-3-(nonyloxy)p ropoxy)hexanoate, (19Z,22Z)-N,N-dimethyloctacosa-19,22-dien-7-amine, 4-((N-(2-(Dinonylamino)ethyl)-N- nonylglycyl)oxy)pentan-2-yldinonylglycinate, 3-Hydroxybutan-2-ylN-(2- (dinonylamino)ethyl)-N-nonyl, Di(heptadecan-9-yl)8,8'-(26,28-dimethyl-ll,24,30,43-tetraoxo - 10,25,29,44-tetraoxa-19,35-diazatripentacontane-19,35-diyl)d ioctanoate, Di(heptadecan-9- yl)8,8'-(26,27-dimethyl-ll,24,29,42-tetraoxo-10,25,28,43-tet raoxa-19,34- diazadopentacontane-19,34-diyl)dioctanoate, Di(heptadecan-9-yl)8,8'-(ll,24,29,42-tetraoxo- 10,25,28,43-tetraoxa-19,34-diazadopentacontane-19,34-diyl)di octanoate, Di(heptadecan-9- yl)8,8'-((piperazine-l,4-diylbis(5-oxopentane-5,l-diyl))bis( (8-(nonyloxy)-8- oxooctyl)azanediyl))dioctanoate, Di(heptadecan-9-yl)15,18-dimethyl-9,24-bis(8-(nonyloxy)- 8-oxooctyl)-14,19-dioxo-9,15,18,24-tetraazadotriacontanedioa te, Di(heptadecan-9-yl)15,19- dimethyl-9,25-bis(8-(nonyloxy)-8-oxooctyl)-14,20-dioxo-9,15, 19,25- tetraazatritriacontanedioate, Di(heptadecan-9-yl)15,18-diethyl-9,24-bis(8-(nonyloxy)-8- oxooctyl)-14,19-dioxo-9,15,18,24-tetraazadotriacontanedioate , N,N-dimethyl-3-{[(9Z,12Z)- octadeca-9,12-dien-1-yloxy]methyl}dodecan-1-amine, methyl8-[2-(ll-{[4- (dimethylamino)butanoyl]oxy}octadecyl)cyclopropyl]octanoate, methyl8-{2-[ll- (dimethylamino)heptadecyl]cyclopropyl}octanoate(Compound18); , Heptadecan-9-yl8-((2- hydroxyethyl)(8-(nonyloxy)-8-oxooctyl)amino)octanoate, (2-octylcyclopropyl)methyl6-(2- (dimethylamino)-3-(heptyloxy)propoxy)hexanoate, (17Z)-N,N-dimethylhexacos-17-en-9- amine, N1-(2-(4-(2-(Didodecylamino)ethyl)piperazin-1-yl)ethyl)-N1^V 2,N2-trihexylethane- 1,2-diamine, N,N-dimethyl-2-{[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]methyl} undecan-1- amine, methyl8-{2-[ll-(dimethylamino)octadecyl]cyclopropyl}octanoat e, (2- octylcyclopropyl)methyl6-(2-(dimethylamino)-3-(hexyloxy)prop oxy)hexanoate, (18Z)-N,N- dimethylheptacos-18-en-10-amine, 2-((2- (Dinonylamino)ethyl)(nonyl)amino)ethyltetradecanoate, 2-((2- (Dinonylamino)ethyl)(nonyl)amino)ethylnonanoate, TetradecylN-(2-(dinonylamino)ethyl)-N- nonylglycinate, NonylN-(2-(dinonylamino)ethyl)-N-nonylglycinate, 4-(2-((2- (dinonylamino)ethyl)(nonyl)amino)acetamido)butylpentanoate, 1,1'-(Piperazine-1,4-diyl)bis(5- (didecylamino)pentan-1-one, 2-((2-(dinonylamino)ethyl)(nonyl)armno)-N- tetradecylacetamide, N-decyl-2-((2-(dinonylamino)ethyl)(nonyl)amino), N1-(3-(3- (dinonylamino)propoxy)propyl)-N1,N2,N2-trinonylethane-1,2-di amine, N1-(2- (dinonylamino)ethyl)-N\N8,N8-trinonyloctane-1,8-diamine, methyl8-[2-(ll-{[4- (dimethylamino)butanoyl]oxy}nonadecyl)cyclopropyl]octanoate, methyl8-{2-[ll- (dimethylamino)nonadecyl]cyclopropyl}octanoate, (Z)-undec-2-en-1-yl6-(3-(decyloxy)-2- (dimethylamino)propoxy)hexanoate, (2R,12Z,15Z)-N,N-dimethyl-1-(undecyloxy)henicosa- 12,15-dien-2-amine, (21Z,24Z)-N,N-dimethyltriaconta-21,24-dien-9-amine, 2- (dinonylamino)-N-(4-(2-((2-(dinonylamino)ethyl)(nonyl)amino) -N-methylacetamido)butyl)- N-methylacetamide, 7,10-dimethyl-13,16-dinonyl-6,ll-dioxo-4-tetradecyl-4,7,10,1 3,16- pentaazapentacosyldecanoate, 2-(dinonylamino)-N-(2-(2-((2- (dinonylamino)ethyl)(nonyl)amino)-N-ethylacetamido)ethyl)-N- ethylacetamide, 2- (dinonylamino)-N-(3-(2-((2-(dinonylamino)ethyl)(nonyl)amino) -N- methylacetamido)propyl)-N-methylacetamide, 2-((2-(di((Z)-non-3-en-1-yl)amino)ethyl)((Z)- non-3-en-1-yl)amino)-N-(2-(2-(dinonylamino)-N-methylacetamid o)ethyl)-N- methylacetamide, 2-(dinonylamino)-N-(2-(2-((2- (dinonylamino)ethyl)(nonyl)amino)acetamido)ethyl)acetamide, Pentyl8,1l-dimethyl-5,14,17- trinonyl-7,12-dioxo-5,8,l1,14,17-pentaazahexacosanoate2-((2- (Dinonylamino)ethyl)(nonyl)aniino)-N-methyl-N-(2-(methylandn o)ethyl)acetami, 2- (Dinonylamino)-N-(2-(2-((2-(dinonylamino)ethyl)(nonyl)amino) -N-methylacetamido)ethyl)- N-methylacetamide2-(Dinonylamino)-N-methyl-N-(2-(methylamino )ethyl)acetamide, 2-((N- (2-(Dinonylamino)ethyl)-N-nonylglycyl)oxy)ethyldinonylglycin ate2- Hydroxyethyldinonylglycinate, methyl8-[2-(ll-{[4- (dimethylamino)butanoyl]oxy}icosyl)cyclopropyl]octanoate, methyl8-{2-[ll- (dimethylamino)icosyl]cyclopropyl}octanoate, (Z)-undec-2-en-1-yl6-(2-(dimethylamino)-3- (nonyloxy)propoxy)hexanoate, (2R,12Z,15Z)-1-(hexadecyloxy)-N,N-dimethylhenicosa- 12,15-dien-2-amine, (22Z,25Z)-N,N-dimethylhentriaconta-22,25-dien-10-amine, l,l- (Piperazine-l,4-diyl)bis(4-(didecylamino)butan-1-one)fert-Bu tyl4-(didecylaminobutanoate, Heptyl5-(4-(N-(2-(dinonylamino)ethyl)-N-nonylglycyl)piperazi n-1-yl)-5-oxopentanoate5- (Heptloxy)-5-oxopentanoicacid, Heptyl5-(4-(N-(2-(dinonylamino)ethyl)-N- nonylglycyl)piperazin-1-yl)-5-oxopentanoate5-(Heptloxy)-5-ox opentanoic, (Z)-4-((2-(4-(N- (2-(dinonylamino)ethyl)-N-nonylglycyl)piperazin-1-yl)-2-oxoe thyl)(tetradecyl)amino)but-2- en-1-y1nonanoate(Z)-4-Hydroxybut-2-en-1-ylnonanoate, (Z)-3-((2-(4-(N-(2- (Dinonylamino)ethyl)-N-nonylglycyl)piperazin-1-yl)-2-oxoethy l)(tetradec-9-en-1- yl)amino)propy1decanoate(Z)-Tetradec-9-en-1-ylmethanesulfona te, methyl8-[2-(9-{[4- (dimethylamino)butanoyl]oxy}pentadecyl)cyclopropyl]octanoate , methyl8-{2-[9- (dimethylamino)pentadecyl]cyclopropyl}octanoate, (Z)-undec-2-en-1-yl6-(2- (dimethylamino)-3-(heptyloxy)propoxy)hexanoate, (2R,12Z,15Z)-1-(hexyloxy)-N,N- dimethylhenicosa-12,15-dien-2-amine, (16Z,19Z)-N,N-dimethylpentacosa-16,19-dien-6- amine, Methyl8-((2-(4-(N-(2-(Di((Z)-non-3-en-1-yl)amino)ethyl)-N-(( Z)-non-3-en-1- yl)glycyl)piperazin-1-yl)-2-oxoethyl)(nonyl)amino)octanoatef ert-Butyl4- (nonylglycyl)piperazine-1-carboxylate, 3-((2-(4-(N-(2-(Dinonylamino)ethyl)-N- nonylglycyl)piperazin-1-yl)-2-oxoethyl)(tetradecyl)amino)pro pyl(Z)-dec-3-enoate(Z)-Dec-3- en-1-ol, 2-((2-(Di((Z)-non-3-en-1-yl)amino)ethyl)((Z)-non-3-en-1-yl)a mino)-1-(4- (dinonylglycyl)piperazin-1-yl)ethan-1-one(Z)-1-Bromonon-4-en e, 3-((2-(4-(N-(2- (Dinonylamino)ethyl)-N-nonylglycyl)piperazin- oxoethyl)(dodecyl)amino)propyloctanoatetot-Butyldodecylglyci nate, S-Pentyl4-((2-(4-(N-(2- (dinonylamino)ethyl)-N-nonylglycyl)piperazin-1-yl)-2-oxoethy l)(nonyl)amino)butanethioate, 3-((2-(l-(N-(2-(Dinonylamino)ethyl)-N-nonylglycyl)piperidin- ^yl)ethyl)(nonyl)amino)propyl3-methylhexanoatefert-Butyl4-(2 -((3-((3- methylhexanoyl)oxy)propyl)(nonyl)amino)ethyl)piperidine-1-, 3-((2-(l-(N-(2- (Dinonylamino)ethyl)-N-nonylglycyl)piperidin-4-yl)ethyl)(non yl)amino)-2- methylpropylhexanoate, 3-((2-(4-(N-(2-(Dinonylamino)ethyl)-N-nonylglycyl)piperazin- oxoethyl)(nonyl)amino)propyl3-methylhexanoate, 3-((2-(4-(N-(2-(Dinonylamino)ethyl)-N- nonylglycyl)piperazin-oxoethyl)(nonyl)amino)-2-methylpropylh exanoate, methyl8-[2-(9-{[4- (dimethylamino)butanoyl]oxy}hexadecyl)cyclopropyl]octanoate, methyl8-{2-[9- (dimethylamino)hexadecyl]cyclopropyl}octanoate, (Z)-undec-2-en-1-yl6-(2-(dimethylamino)- 3-(hexyloxy)propoxy)hexanoate, (2R,12Z,15Z)-1-(decyloxy)-N,N-dimethylhenicosa-l2,15- dien-2-amine, (17Z,20Z)-N,N-dimethylhexacosa-17,20-dien-7-amine, 2-((2- (Dinonylamino)ethyl)(nonyl)amino)ethyl1-(dinonylglycyl)piper idine-4-carboxylate, l-(2- (Dinonylamino)ethyl)4-(2-((2-(dinonylamino)ethyl)(nonyl)amin o)ethyl)cyclohexane-1,4- dicarboxylate2-(Dinonylamino)ethan-1-ol, Methyl12-((2-(l-(N-(2-(dinonylamino)ethyl)-N- nonylglycyl)pyrrolidin-3-yl)ethyl)(tetradecyl)amino)dodecano atefert-Butyl3-(2-((12- methoxy-12-oxododecyl)(tetradecyl)amino)ethyl)pyrrolidine-1- carboxylate, 3-((2-(l-(N-(2- (Dinonylamino)ethyl)-N-nonylglycyl)pyrrolidin-3- yl)ethyl)(tetradecyl)amino)propyldecanoateter/-Butyl3-(2-((3 - (decanoyloxy)propyl)(tetradecyl)amino)ethyl)pyrrolidine-1-ca rboxylate, "Heptyl6-((2-(l-(N- (2-(dinonylamino)ethyl)-N-nonylglycyl)pyrrolidin-3- yl)ethyl)(tetradecyl)amino)hexanoatetot-Butyl3-(2-((6-(hepty loxy)-6- oxohexyl)(tetradecyl)amino)ethyl)pyrrolidine-1-carboxylate, ", Pentyl8-((2-(l-(N-(2- (dinonylamino)ethyl)-N-nonylglycyl)pyrrolidin-3-yl)ethyl)(te tradecyl)amino)octanoate/er/- Butyl3-(2-(tetradecylamino)ethyl)pyrrolidine-1-carboxylate, Methyl12-((2-(l-(N-(2- (dinonylamino)ethyl)-N-nonylglycyl)piperidin-3-yl)ethyl)(tet radecyl)amino)dodecanoate- Butyl3-(2-((12-methoxy-12-oxododecyl)(tetradecyl)amino)ethyl )piperidine-1-carboxylate, 3- ((2-(l-(N-(2-(Dinonylamino)ethyl)-N-nonylglycyl)piperidin-3- yl)ethyl)(tetradecyl)amino)propyldecanoate, Heptyl6-((2-(l-(N-(2-(dinonylamino)ethyl)-N- nonylglycyl)piperidin-3-yl)ethyl)(tetradecyl)amino)hexanoate , Pentyl8-((2-(l-(N-(2- (dinonylamino)ethyl)-N-nonylglycyl)piperidin-3-yl)ethyl)(tet radecyl)amino)octanoate, Pentyl6-((2-(4-(2-((2-(didodecylamino)ethyl)(dodecyl)amino)e thyl)piperazin-1- yl)ethyl)(dodecyl)amino)hexanoateStep1:Pentyl6-bromohexanoat e, methyl8-[2-(9-{[4- (dimethylamino)butanoyl]oxy}heptadecyl)cyclopropyl]octanoate , methyl8-{2-[9- (dimethylamino)heptadecyl]cyclopropyl}octanoate, (2S,12Z,15Z)-N,N-dimethyl-1- (octyloxy)henicosa-12,15-dien-2-amine, (2-octylcyclopropyl)methyl6-(2-(dimethylamino)-3- (octyloxy)propoxy)hexanoate, (18Z,21Z)-N,N-dimethylheptacosa-18,21-dien-8-amine, trans- 1-methyl-3,4-bis(((Z)-hexadec-9-enoyloxy)methyl)pyrrolidine, (Z)-Non-2-en-1-yl4-((2-(4-(N- (2-(dinonylamino)ethyl)-N-nonylglycyl)piperazin-1-yl)-2- oxoethyl)(tetradecyl)amino)butanoate, trans-1-methyl-3,4-bis(((9Z,12Z)-octadeca-9,12- dienoyloxy)methyl)pyrrolidine, Methyl12-((2-(4-(N-(2-(dinonylamino)ethyl)-N- nonylglycyl)piperazin-1-yl)-2-oxoethyl)(tetradecyl)amino)dod ecanoate, ethyl(7Z)-17-[2- (dimethylamino)ethyl]hexacos-7-enoate, trans-1-methyl-3,4-bis(((Z)-octadeca-9- enoyloxy)methyl)pyrrolidine, methyl6-(2-{]11-^2- (dimethylamino)ethyl]icosyl}cyclopropyl)hexanoate, Methyl12-((2-(l-(N-(2- (dinonylamino)ethyl)-N-nonylglycyl)piperidin-4-yl)ethyl)(tet radecyl)amino)dodecanoate, methyl10-(2-V-^2-(dimethylamino)ethyl]hexadecyl}cyclopropyl) decanoate, methyl8-(2- {111-;2-(dimethylamino)ethyl]heptadecyl}cyclopropyl)octanoat e, 2-(l-(N-(2- (Dinonylamino)ethyl)-N-nonylglycyl)piperidin-4-yl)ethyldinon ylglycinatefert-Butyl4-(2- ((dinonylglycyl)oxy)ethyl)piperidine-1-carboxylate, methyl8-(2-{lLl-;2- (dimethylamino)ethyl]octadecyl}cyclopropyl)octanoate, methyl8-(2-{l11- "2- (dimethylamino)ethyl]nonadecyl}cyclopropyl)octanoate, l,-(piperazine-l,4-diyl)bis(2- (dinonylamino)ethan-1-one), methyl8-[2-{]11-^2- (dimethylamino)ethyl]icosyl}cyclopropyl)octanoate, methyl8-(2-{9-[2- (dimethylamino)ethyl]pentadecyl}cyclopropyl)octanoate, methyl(7Z)-19-{[4- (dimethylamino)butanoyl]oxy}octacos-7-enoate, methyl(7Z)-19-(dimethylamino)octacos-7- enoate, cis-1-methyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-4-(octy loxy)pyrrolidine, 2- (Didodecylamino)-1-(4-(N-(2-(didodecylamino)ethyl)-N-dodecyl glycyl)piperazin-1-yl)ethan- 1-one, (Z)-undec-2-en-1-yl6-(2-(dimethylamino)-3-(octyloxy)propoxy) hexanoate, (2SN,N- dimethyl-1-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]decan-2-amin e(Compound11), (19Z,22Z)- N,N-dimeihyloctacosa-19,22-dien-9-amine, methyl8-(2-{9-[2- (dimethylamino)ethyl]hexadecyl}cyclopropyl)octanoate, 5-((2-(4-(N-(2- (Dinonylamino)ethyl)-N-nonylglycyl)piperazin- oxoethyl)(nonyl)amino)pentylmethylcarbonate, methyl8-(2-{9-[2- (dimethylamino)ethyl]heptadecyl}cyclopropyl)octanoate, methyl(7Z)-19-[2- (dimethylamino)ethyl]octacos-7-enoate, (Z)-Pent-2-en-1-yl4-((2-(4-(N-(2- (dinonylamino)ethyl)-N-nonylglycyl)piperazin-1-yl)-2-oxoethy l)(nonyl)amino)butanoate, methyl(1lZ)-19-[2-(dimethylamino)ethyl]octacos-l1-enoate, methyl(9Z)-21-[2- (dimethylamino)ethyl]heptacos-9-enoate, methyl(9Z)-21-[2-(dimethylamino)ethyl]octacos-9- enoate, methyl(9Z)-21-[2-(dimethylamino)ethyl]nonacos-9-enoate, 2-(l-(N-(2- (Dinonylamino)ethyl)-N-nonylglycyl)pyrrolidin-3-yl)ethyldino nylglycinate, methyl(9Z)-21- [2-(dimethylamino)ethyl]triacont-9-enoate, (l-(N-(2-(Dinonylamino)ethyl)-N- nonylglycyl)pyrrolidin-3-yl)methyldinonylglycinate, methyl(9Z)-19-[2- (dimethylamino)ethyl]pentacos-9-enoate, methyl(9Z)-19-[2-(dimethylamino)ethyl]hexacos-9- enoate, methyl6-(2-(8-(3-(decyloxy)-2- (dimethylamino)propoxy)octyl)cyclopropyl)hexanoate, methyl(1lZ)-19-{[4- (dimethylamino)butanoyl]oxy}octacos-l1-enoate, methyl(1lZ)-19-(dimethylamino)octacos- l1-enoate, (2S)-N,N-dimethyl-1-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]dod ecan-2-amine, (14Z,17Z)-N,N-dimethyltricosa-14,17-dien-4-amine, Methyldi((9Z,12Z)-octadeca-9,12- dienyl)amine, methyl(9Z)-19-{[4-(dimethylamino)butanoyl]oxy}octacos-9-enoa te, methyl(9Z)-19-(dimethylamino)octacos-9-enoate, (Z)-methyl17-(2-(dimethylamino)-3- (octyloxy)propoxy)heptadec-8-enoate, (3R,4R)-3,4-bis((Z)-hexadec-9-enyloxy)-1- methylpyrrolidine, (2S)-N,N-dimethyl-1-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]und ecan-2- amine, (20Z,23Z)-nonacosa-20,23-dien-10-yl4-(dimethylamino)butanoat e, (20Z,23Z)-N,N- dimethylnonacosa-20,23-dien-10-amine, 3-((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31- tetraen-19-yloxy)-N,N-dimethylpropan-1-amine, 3-((6Z,9Z,28Z,31Z)-heptatriaconta- 6,9,28,31-tetraen-19-yloxy)-N,N-dimethylpropan-1-amine, (6Z,9Z,28Z,31Z)-heptatriaconta- 6,9,28,31-tetraen-19-yl4-(dimethylamino)butanoate), (6Z,16Z)-12-((Z)-dec-4-enyl)docosa- 6,16-dien-l1-yl5-(dimethylamino)pentanoate, (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien- l1-yl5-(dimethylamino)pentanoat, (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-yl5- (dimethylamino)pentanoate, L-arginine-alpha-(2,3-dilauryloxy)propylamide, L-lysine-alpha- (2,3-dilauryloxy)propylamide, 2,3-dioleyloxypropylamine, 2,3-distearyloxypropylamine, 2,3- dilauryloxypropylamine, dilinoleylmethyl4-(dimethylamino)propylether), dilinoleylmethyl4- (dimethylamino)butylether), and 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane. [0684] In some embodiments, the at least one non-cationic lipid comprises at least one phospholipid, at least one fusogenic lipid, at least one anionic lipid, at least one helper lipid, at least one neutral lipid, or any combination thereof. In some embodiments, the LNP may be essentially devoid of the at least one non-cationic lipid. In some embodiments, the LNP may contain no amount of the at least one non-cationic lipid. [0685] In some embodiments, at least one non-cationic lipid may be selected from, but is not limited to, at least one of 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), DSPC but with 3 unsaturated double bonds pertail (18:3 PC), Acylcarnosine (AC), 1- hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), N-oleoyl-SPM (C18:l), N- lignocerylSPM (C24:0), N-nervacylC (C24:l), carbamoyl]cholesterol (Cet-P), cholesterolhemisuccinate (CHEMS), cholesterol (Chol), Cholesterolhemidodecanedicarboxylic acid (Chol-C12), 12- Cholesteryloxycarbonylaminododecanoic acid (Chol-C13N), Cholesterolhemioxalate (Chol- C2), Cholesterolhemimalonate (Chol-C3), N-(Cholesteryl-oxycarbonyl)glycine (Chol-C3N), Cholesterolhemiglutarate (Chol-C5), Cholesterolhemiadipate (Chol-C6), Cholesterolhemipimelate (Chol-C7), Cholesterolhemisuberate (Chol-C8), Cardiolipid (CL), 1,2-bis(tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine (DC8-9PC), dicetylphosphate (DCP), dihexadecylphosphate (DCP1), 1,2-Dipalmitoyglycerol-3-hemisuccinate (DGSucc), short-chainbis-n-heptadecanoylphosphatidylcholine (DHPC), dihexadecoylphosphoethanolamine (DHPE), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dilauroyl-sn-glycero-3-PE (DLPE), Dimyristoylglycerolhemisuccinate (DMGS), dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphoethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dioleyloxybenzylalcohol (DOBA), 1,2- dioleoylglyceryl-3-hemisuccinate (DOGHEMS), N-[2~(2-{2-[2-(2,3-Bis-octadec-9-enyloxy- propoxy)-ethoxy]-ethoxy}-ethoxy)-ethyl]-3-(3,4,5-1rihydroxy- 6-hydroxymethyl-1etrahydro- pyran-2-ylsulfanyl)-propionamide (DOGP4αMan), dioleoylphosphatidylcholine (DOPC), dioleoylphosphatidylethanolamine (DOPE), dioleoyl-phosphatidylethanolamine4-(N- maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dioleoylphosphatidylglycerol (DOPG), 1,2-dioleoyl-sn-glycero-3-(phospho-L-serine) (DOPS), acell-fusogenicphospholipid (DPhPE), dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylcholine (DSPC), distearoyl-phosphatidyl-ethanolamine (DSPE), distearoylphosphoethanolamineimidazole (DSPEI), 1,2-diundecanoyl-sn-glycero- phosphocholine (DUPC), eggphosphatidylcholine (EPC), N-histidinylcholesterolcarbamate (HCChol), histaminedistearoylglycerol (HDSG), N-histidinylcholesterolhemisuccinate (HistChol), 1,2-Dipalmitoylglycerol-hemisuccinate-Nα-Histidinyl-Hemisuc cinate (HistSuccDG), N-(5'-hydroxy-3'-oxypentyl)-10-12-pentacosadiynamide (h-Pegi-PCDA), 2-[l- hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH), hydrogenatedsoybeanphosphatidylcholine (HSPC), 1,2-Dipalmitoylglycerol-Oα-histidinyl- Nα-hemisuccinate (IsohistsuccDG), mannosialized dipalmitoylphosphatidylethanolamine (ManDOG), 1,2-Dioleoyl-sn-Glycero-3-Phosphoethanolamine-N-[4-(p- maleimidomethyl)cyclohexane-carboxamide] (MCC-PE), 1,2-diphytanoyl-sn-glycero-3- phosphoethanolamine (ME 16.0 PE), 1-myristoyl-2-hydroxy-sn-glycero-phosphocholine (MHPC), a thiol-reactive maleimide head group lipid, e.g., 1,2-dioleoyl-sn-glycero-3- phosphoethanolamine-N-[4-(p-maleimidophenyl)but-yramid (MPB-PE), Nervonic Acid (NA), sodiumcholate (NaChol), 1,2-dioleoyl-sn-glycero-3-[phosphoethanolamine-N-dodecanoyl (NC12-DOPE), defined by synthesis example in WO2008042973A2 (ND98), "N- glutarylphosphatidylethanolamine(s) of Formula 1" (NG-PE), N-hydroxysulfosuccinimide (NHS-'x'), "N~(co)-dicarboxylicacid-derivatized phosphatidylethanolamines encompassed by Formula 1" (NωPE-'x'), OleicAcid (OA), 1-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3- phosphocholine (OChemsPC), phosphatidicacid (PA), phosphatidylethanolamine lipid (PE), PE lipid conjugated with polyethyleneglycol (PEG). One example of PEG-PE can be polyethyleneglycol-distearoylphosphatidylethanolamine lipid (PEG-PE), phosphatidylglycerol (PG), partially hydrogenated soy phosphatidylchloline (PHSPC), phosphatidylinositol lipid (PI), phosphotidylinositol-4-phosphate (PIP), palmitoyloleoylphosphatidylcholine (POPC), phosphatidylethanolamine (POPE), palmitoyloleyolphosphatidylglycerol (POPG), phosphatidylserine (PS), lissaminerhodamineB-phosphatidylethanolamine lipid (Rh-PE), purifiedsoy-derived mixture of phospholipids (SIOO), phosphatidylcholine (SM), 18-1-transPE,1-stearoyl-2-oleoyl- phosphatidyethanolamine (SOPE), soybeanphosphatidylcholine (SPC), sphingomyelins (SPM), alpha.alpha'-trehalose6,6'-dibehenate (TDB), 1,2-dielaidoyl-sn-glycero-3- phophoethanolamine (transDOPE), ((23S,5R)-3-(bis(hexadecyloxy)methoxy)-5-(5-methyl- 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl )methylmethylphosphate, 1,2- diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3- phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2- didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3- phosphocholine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn- glycero-3-phosphoethanolamine, 1,2-dioleyl-sn-glycero-3-phosphoethanolamine, 1,2- distearoyl-sn-glycero-3-phosphoethanolamine, 16-O-monomethyl PE, 16-O-dimethyl PE, and dioleylphosphatidylethanolamine. [0686] In some embodiments, the LNP comprises an ionizable lipid or lipid-like material. As a non-limiting example, the ionizable lipid may be C12-200, CKK-E12, 5A2-SC8, BAMEA- 016B, or 7C1. Other ionizable lipids are known in the art and are useful herein. [0687] In some embodiments, the LNP comprises a phospholipid. As a non-limiting example, the phospholipid (helper) may be DOPE, DSPC, DOTAP, or DOTMA. [0688] In some embodiments, the LNP comprises a PEG derivative. As a non-limiting example, the PEG derivative may be a lipid-anchored such as PEG is C14-PEG2000, C14- PEG1000, C14-PEG3000, C14-PEG5000, C12-PEG1000, C12-PEG2000, C12-PEG3000, C12-PEG5000, C16-PEG1000, C16-PEG2000, C16-PEG3000, C16-PEG5000, C18- PEG1000, C18-PEG2000, C18-PEG3000, or C18-PEG5000. [0689] In some embodiments, the at least one sterol comprises at least one cholesterol or cholesterol derivative. In some embodiments, the LNP may be essentially devoid of an at least one sterol. In some embodiments, the LNP may contain no amount of the at least one sterol. [0690] In some embodiments, the at least one particle-activity-modifying-agent comprises at least one component that reduced aggregation of particles, at least one component that decreases clearing of the LNP from circulation in a subject, at least component that increases the LNP's ability to traverse mucus layers, at least one component that decreases a subjects immune response to administration of the LNP, at least one component that modifies membrane fluidity of the LNP, at least one component that contributes to the stability of the LNP, or any combination thereof. In some embodiments, the LNP may be essentially devoid of the at least one particle-activity-modifying-agent. In some embodiments, the LNP may contain no amount of the at least one particle-activity-modifying-agent. [0691] In some embodiments, the particle-activity-modifying-agent may be comprised of a polymer. In some embodiments, the polymer comprising the particle-activity-modifying-agent may be comprised of at least one polyethylene glycol (PEG), at least one polypropylene glycol (PPG), poly(2-oxazoline) (POZ), at least one polyamide (ATTA), at least one cationic polymer, or any combination thereof. [0692] In some embodiments, the average molecular weight of the polymer moiety (e.g., PEG) may be between 500 and 20,000 daltons. In some embodiments, the molecular weight of the polymer may be about 500 to 20,000, 1,000 to 20,000, 1,500 to 20,000, 2,000 to 20,000, 2,500 to 20,000, 3,000 to 20,000, 3,500 to 20,000, 4,000 to 20,000, 4,500 to 20,000, 5,000 to 20,000, 5,500 to 20,000, 6,000 to 20,000, 6,500 to 20,000, 7,000 to 20,000, 7,500 to 20,000, 8,000 to 20,000, 8,500 to 20,000, 9,000 to 20,000, 9,500 to 20,000, 10,000 to 20,000, 10,500 to 20,000, 11,000 to 20,000, 11,500 to 20,000, 12,000 to 20,000, 12,500 to 20,000, 13,000 to 20,000, 13,500 to 20,000, 14,000 to 20,000, 14,500 to 20,000, 15,000 to 20,000, 15,500 to 20,000, 16,000 to 20,000, 16,500 to 20,000, 17,000 to 20,000, 17,500 to 20,000, 18,000 to 20,000, 18,500 to 20,000, 19,000 to 20,000, 19,500 to 20,000, 500 to 19,500, 1,000 to 19,500, 1,500 to 19,500, 2,000 to 19,500, 2,500 to 19,500, 3,000 to 19,500, 3,500 to 19,500, 4,000 to 19,500, 4,500 to 19,500, 5,000 to 19,500, 5,500 to 19,500, 6,000 to 19,500, 6,500 to 19,500, 7,000 to 19,500, 7,500 to 19,500, 8,000 to 19,500, 8,500 to 19,500, 9,000 to 19,500, 9,500 to 19,500, 10,000 to 19,500, 10,500 to 19,500, 11,000 to 19,500, 11,500 to 19,500, 12,000 to 19,500, 12,500 to 19,500, 13,000 to 19,500, 13,500 to 19,500, 14,000 to 19,500, 14,500 to 19,500, 15,000 to 19,500, 15,500 to 19,500, 16,000 to 19,500, 16,500 to 19,500, 17,000 to 19,500, 17,500 to 19,500, 18,000 to 19,500, 18,500 to 19,500, 19,000 to 19,500, 1,500 to 19,000, 2,000 to 19,000, 2,500 to 19,000, 3,000 to 19,000, 3,500 to 19,000, 4,000 to 19,000, 4,500 to 19,000, 5,000 to 19,000, 5,500 to 19,000, 6,000 to 19,000, 6,500 to 19,000, 7,000 to 19,000, 7,500 to 19,000, 8,000 to 19,000, 8,500 to 19,000, 9,000 to 19,000, 9,500 to 19,000, 10,000 to 19,000, 10,500 to 19,000, 11,000 to 19,000, 11,500 to 19,000, 12,000 to 19,000, 12,500 to 19,000, 13,000 to 19,000, 13,500 to 19,000, 14,000 to 19,000, 14,500 to 19,000, 15,000 to 19,000, 15,500 to 19,000, 16,000 to 19,000, 16,500 to 19,000, 17,000 to 19,000, 17,500 to 19,000, 18,000 to 19,000, 18,500 to 19,000, 1,500 to 18,500, 2,000 to 18,500, 2,500 to 18,500, 3,000 to 18,500, 3,500 to 18,500, 4,000 to 18,500, 4,500 to 18,500, 5,000 to 18,500, 5,500 to 18,500, 6,000 to 18,500, 6,500 to 18,500, 7,000 to 18,500, 7,500 to 18,500, 8,000 to 18,500, 8,500 to 18,500, 9,000 to 18,500, 9,500 to 18,500, 10,000 to 18,500, 10,500 to 18,500, 11,000 to 18,500, 11,500 to 18,500, 12,000 to 18,500, 12,500 to 18,500, 13,000 to 18,500, 13,500 to 18,500, 14,000 to 18,500, 14,500 to 18,500, 15,000 to 18,500, 15,500 to 18,500, 16,000 to 18,500, 16,500 to 18,500, 17,000 to 18,500, 17,500 to 18,500, 18,000 to 18,500, 1,500 to 18,000, 2,000 to 18,000, 2,500 to 18,000, 3,000 to 18,000, 3,500 to 18,000, 4,000 to 18,000, 4,500 to 18,000, 5,000 to 18,000, 5,500 to 18,000, 6,000 to 18,000, 6,500 to 18,000, 7,000 to 18,000, 7,500 to 18,000, 8,000 to 18,000, 8,500 to 18,000, 9,000 to 18,000, 9,500 to 18,000, 10,000 to 18,000, 10,500 to 18,000, 11,000 to 18,000, 11,500 to 18,000, 12,000 to 18,000, 12,500 to 18,000, 13,000 to 18,000, 13,500 to 18,000, 14,000 to 18,000, 14,500 to 18,000, 15,000 to 18,000, 15,500 to 18,000, 16,000 to 18,000, 16,500 to 18,000, 17,000 to 18,000, 17,500 to 18,000, 1,500 to 17,500, 2,000 to 17,500, 2,500 to 17,500, 3,000 to 17,500, 3,500 to 17,500, 4,000 to 17,500, 4,500 to 17,500, 5,000 to 17,500, 5,500 to 17,500, 6,000 to 17,500, 6,500 to 17,500, 7,000 to 17,500, 7,500 to 17,500, 8,000 to 17,500, 8,500 to 17,500, 9,000 to 17,500, 9,500 to 17,500, 10,000 to 17,500, 10,500 to 17,500, 11,000 to 17,500, 11,500 to 17,500, 12,000 to 17,500, 12,500 to 17,500, 13,000 to 17,500, 13,500 to 17,500, 14,000 to 17,500, 14,500 to 17,500, 15,000 to 17,500, 15,500 to 17,500, 16,000 to 17,500, 16,500 to 17,500, 17,000 to 17,500, 1,500 to 17,000, 2,000 to 17,000, 2,500 to 17,000, 3,000 to 17,000, 3,500 to 17,000, 4,000 to 17,000, 4,500 to 17,000, 5,000 to 17,000, 5,500 to 17,000, 6,000 to 17,000, 6,500 to 17,000, 7,000 to 17,000, 7,500 to 17,000, 8,000 to 17,000, 8,500 to 17,000, 9,000 to 17,000, 9,500 to 17,000, 10,000 to 17,000, 10,500 to 17,000, 11,000 to 17,000, 11,500 to 17,000, 12,000 to 17,000, 12,500 to 17,000, 13,000 to 17,000, 13,500 to 17,000, 14,000 to 17,000, 14,500 to 17,000, 15,000 to 17,000, 15,500 to 17,000, 16,000 to 17,000, 16,500 to 17,000, 1,500 to 16,500, 2,000 to 16,500, 2,500 to 16,500, 3,000 to 16,500, 3,500 to 16,500, 4,000 to 16,500, 4,500 to 16,500, 5,000 to 16,500, 5,500 to 16,500, 6,000 to 16,500, 6,500 to 16,500, 7,000 to 16,500, 7,500 to 16,500, 8,000 to 16,500, 8,500 to 16,500, 9,000 to 16,500, 9,500 to 16,500, 10,000 to 16,500, 10,500 to 16,500, 11,000 to 16,500, 11,500 to 16,500, 12,000 to 16,500, 12,500 to 16,500, 13,000 to 16,500, 13,500 to 16,500, 14,000 to 16,500, 14,500 to 16,500, 15,000 to 16,500, 15,500 to 16,500, 16,000 to 16,500, 1,500 to 16,000, 2,000 to 16,000, 2,500 to 16,000, 3,000 to 16,000, 3,500 to 16,000, 4,000 to 16,000, 4,500 to 16,000, 5,000 to 16,000, 5,500 to 16,000, 6,000 to 16,000, 6,500 to 16,000, 7,000 to 16,000, 7,500 to 16,000, 8,000 to 16,000, 8,500 to 16,000, 9,000 to 16,000, 9,500 to 16,000, 10,000 to 16,000, 10,500 to 16,000, 11,000 to 16,000, 11,500 to 16,000, 12,000 to 16,000, 12,500 to 16,000, 13,000 to 16,000, 13,500 to 16,000, 14,000 to 16,000, 14,500 to 16,000, 15,000 to 16,000, 15,500 to 16,000, 1,500 to 15,500, 2,000 to 15,500, 2,500 to 15,500, 3,000 to 15,500, 3,500 to 15,500, 4,000 to 15,500, 4,500 to 15,500, 5,000 to 15,500, 5,500 to 15,500, 6,000 to 15,500, 6,500 to 15,500, 7,000 to 15,500, 7,500 to 15,500, 8,000 to 15,500, 8,500 to 15,500, 9,000 to 15,500, 9,500 to 15,500, 10,000 to 15,500, 10,500 to 15,500, 11,000 to 15,500, 11,500 to 15,500, 12,000 to 15,500, 12,500 to 15,500, 13,000 to 15,500, 13,500 to 15,500, 14,000 to 15,500, 14,500 to 15,500, 15,000 to 15,500, 1,500 to 15,000, 2,000 to 15,000, 2,500 to 15,000, 3,000 to 15,000, 3,500 to 15,000, 4,000 to 15,000, 4,500 to 15,000, 5,000 to 15,000, 5,500 to 15,000, 6,000 to 15,000, 6,500 to 15,000, 7,000 to 15,000, 7,500 to 15,000, 8,000 to 15,000, 8,500 to 15,000, 9,000 to 15,000, 9,500 to 15,000, 10,000 to 15,000, 10,500 to 15,000, 11,000 to 15,000, 11,500 to 15,000, 12,000 to 15,000, 12,500 to 15,000, 13,000 to 15,000, 13,500 to 15,000, 14,000 to 15,000, 14,500 to 15,000, 1,500 to 14,500, 2,000 to 14,500, 2,500 to 14,500, 3,000 to 14,500, 3,500 to 14,500, 4,000 to 14,500, 4,500 to 14,500, 5,000 to 14,500, 5,500 to 14,500, 6,000 to 14,500, 6,500 to 14,500, 7,000 to 14,500, 7,500 to 14,500, 8,000 to 14,500, 8,500 to 14,500, 9,000 to 14,500, 9,500 to 14,500, 10,000 to 14,500, 10,500 to 14,500, 11,000 to 14,500, 11,500 to 14,500, 12,000 to 14,500, 12,500 to 14,500, 13,000 to 14,500, 13,500 to 14,500, 14,000 to 14,500, 1,500 to 14,000, 2,000 to 14,000, 2,500 to 14,000, 3,000 to 14,000, 3,500 to 14,000, 4,000 to 14,000, 4,500 to 14,000, 5,000 to 14,000, 5,500 to 14,000, 6,000 to 14,000, 6,500 to 14,000, 7,000 to 14,000, 7,500 to 14,000, 8,000 to 14,000, 8,500 to 14,000, 9,000 to 14,000, 9,500 to 14,000, 10,000 to 14,000, 10,500 to 14,000, 11,000 to 14,000, 11,500 to 14,000, 12,000 to 14,000, 12,500 to 14,000, 13,000 to 14,000, 13,500 to 14,000, 1,500 to 13,500, 2,000 to 13,500, 2,500 to 13,500, 3,000 to 13,500, 3,500 to 13,500, 4,000 to 13,500, 4,500 to 13,500, 5,000 to 13,500, 5,500 to 13,500, 6,000 to 13,500, 6,500 to 13,500, 7,000 to 13,500, 7,500 to 13,500, 8,000 to 13,500, 8,500 to 13,500, 9,000 to 13,500, 9,500 to 13,500, 10,000 to 13,500, 10,500 to 13,500, 11,000 to 13,500, 11,500 to 13,500, 12,000 to 13,500, 12,500 to 13,500, 13,000 to 13,500, 1,500 to 13,000, 2,000 to 13,000, 2,500 to 13,000, 3,000 to 13,000, 3,500 to 13,000, 4,000 to 13,000, 4,500 to 13,000, 5,000 to 13,000, 5,500 to 13,000, 6,000 to 13,000, 6,500 to 13,000, 7,000 to 13,000, 7,500 to 13,000, 8,000 to 13,000, 8,500 to 13,000, 9,000 to 13,000, 9,500 to 13,000, 10,000 to 13,000, 10,500 to 13,000, 11,000 to 13,000, 11,500 to 13,000, 12,000 to 13,000, 12,500 to 13,000, 1,500 to 12,500, 2,000 to 12,500, 2,500 to 12,500, 3,000 to 12,500, 3,500 to 12,500, 4,000 to 12,500, 4,500 to 12,500, 5,000 to 12,500, 5,500 to 12,500, 6,000 to 12,500, 6,500 to 12,500, 7,000 to 12,500, 7,500 to 12,500, 8,000 to 12,500, 8,500 to 12,500, 9,000 to 12,500, 9,500 to 12,500, 10,000 to 12,500, 10,500 to 12,500, 11,000 to 12,500, 11,500 to 12,500, 12,000 to 12,500, 1,500 to 12,000, 2,000 to 12,000, 2,500 to 12,000, 3,000 to 12,000, 3,500 to 12,000, 4,000 to 12,000, 4,500 to 12,000, 5,000 to 12,000, 5,500 to 12,000, 6,000 to 12,000, 6,500 to 12,000, 7,000 to 12,000, 7,500 to 12,000, 8,000 to 12,000, 8,500 to 12,000, 9,000 to 12,000, 9,500 to 12,000, 10,000 to 12,000, 10,500 to 12,000, 11,000 to 12,000, 11,500 to 12,000, 1,500 to 11,500, 2,000 to 11,500, 2,500 to 11,500, 3,000 to 11,500, 3,500 to 11,500, 4,000 to 11,500, 4,500 to 11,500, 5,000 to 11,500, 5,500 to 11,500, 6,000 to 11,500, 6,500 to 11,500, 7,000 to 11,500, 7,500 to 11,500, 8,000 to 11,500, 8,500 to 11,500, 9,000 to 11,500, 9,500 to 11,500, 10,000 to 11,500, 10,500 to 11,500, 11,000 to 11,500, 1,500 to 11,000, 2,000 to 11,000, 2,500 to 11,000, 3,000 to 11,000, 3,500 to 11,000, 4,000 to 11,000, 4,500 to 11,000, 5,000 to 11,000, 5,500 to 11,000, 6,000 to 11,000, 6,500 to 11,000, 7,000 to 11,000, 7,500 to 11,000, 8,000 to 11,000, 8,500 to 11,000, 9,000 to 11,000, 9,500 to 11,000, 10,000 to 11,000, 10,500 to 11,000, 1,500 to 10,500, 2,000 to 10,500, 2,500 to 10,500, 3,000 to 10,500, 3,500 to 10,500, 4,000 to 10,500, 4,500 to 10,500, 5,000 to 10,500, 5,500 to 10,500, 6,000 to 10,500, 6,500 to 10,500, 7,000 to 10,500, 7,500 to 10,500, 8,000 to 10,500, 8,500 to 10,500, 9,000 to 10,500, 9,500 to 10,500, 10,000 to 10,500, 1,500 to 10,000, 2,000 to 10,000, 2,500 to 10,000, 3,000 to 10,000, 3,500 to 10,000, 4,000 to 10,000, 4,500 to 10,000, 5,000 to 10,000, 5,500 to 10,000, 6,000 to 10,000, 6,500 to 10,000, 7,000 to 10,000, 7,500 to 10,000, 8,000 to 10,000, 8,500 to 10,000, 9,000 to 10,000, 9,500 to 10,000, 1,500 to 9,500, 2,000 to 9,500, 2,500 to 9,500, 3,000 to 9,500, 3,500 to 9,500, 4,000 to 9,500, 4,500 to 9,500, 5,000 to 9,500, 5,500 to 9,500, 6,000 to 9,500, 6,500 to 9,500, 7,000 to 9,500, 7,500 to 9,500, 8,000 to 9,500, 8,500 to 9,500, 9,000 to 9,500, 1,500 to 9,000, 2,000 to 9,000, 2,500 to 9,000, 3,000 to 9,000, 3,500 to 9,000, 4,000 to 9,000, 4,500 to 9,000, 5,000 to 9,000, 5,500 to 9,000, 6,000 to 9,000, 6,500 to 9,000, 7,000 to 9,000, 7,500 to 9,000, 8,000 to 9,000, 8,500 to 9,000, 1,500 to 8,500, 2,000 to 8,500, 2,500 to 8,500, 3,000 to 8,500, 3,500 to 8,500, 4,000 to 8,500, 4,500 to 8,500, 5,000 to 8,500, 5,500 to 8,500, 6,000 to 8,500, 6,500 to 8,500, 7,000 to 8,500, 7,500 to 8,500, 8,000 to 8,500, 1,500 to 8,000, 2,000 to 8,000, 2,500 to 8,000, 3,000 to 8,000, 3,500 to 8,000, 4,000 to 8,000, 4,500 to 8,000, 5,000 to 8,000, 5,500 to 8,000, 6,000 to 8,000, 6,500 to 8,000, 7,000 to 8,000, 7,500 to 8,000, 1,500 to 7,500, 2,000 to 7,500, 2,500 to 7,500, 3,000 to 7,500, 3,500 to 7,500, 4,000 to 7,500, 4,500 to 7,500, 5,000 to 7,500, 5,500 to 7,500, 6,000 to 7,500, 6,500 to 7,500, 7,000 to 7,500, 1,500 to 7,000, 2,000 to 7,000, 2,500 to 7,000, 3,000 to 7,000, 3,500 to 7,000, 4,000 to 7,000, 4,500 to 7,000, 5,000 to 7,000, 5,500 to 7,000, 6,000 to 7,000, 6,500 to 7,000, 1,500 to 6,500, 2,000 to 6,500, 2,500 to 6,500, 3,000 to 6,500, 3,500 to 6,500, 4,000 to 6,500, 4,500 to 6,500, 5,000 to 6,500, 5,500 to 6,500, 6,000 to 6,500, 1,500 to 6,000, 2,000 to 6,000, 2,500 to 6,000, 3,000 to 6,000, 3,500 to 6,000, 4,000 to 6,000, 4,500 to 6,000, 5,000 to 6,000, 5,500 to 6,000, 1,500 to 5,500, 2,000 to 5,500, 2,500 to 5,500, 3,000 to 5,500, 3,500 to 5,500, 4,000 to 5,500, 4,500 to 5,500, 5,000 to 5,500, 1,500 to 5,000, 2,000 to 5,000, 2,500 to 5,000, 3,000 to 5,000, 3,500 to 5,000, 4,000 to 5,000, 4,500 to 5,000, 1,500 to 4,500, 2,000 to 4,500, 2,500 to 4,500, 3,000 to 4,500, 3,500 to 4,500, 4,000 to 4,500, 1,500 to 4,000, 2,000 to 4,000, 2,500 to 4,000, 3,000 to 4,000, 3,500 to 4,000, 1,500 to 3,500, 2,000 to 3,500, 2,500 to 3,500, 3,000 to 3,500, 1,500 to 3,000, 2,000 to 3,000, 2,500 to 3,000, 1,500 to 2,500, 2,000 to 2,500, and 1,500 to 2,000 daltons. [0693] In some embodiments the polymer (e.g., PEG) is conjugated to at least one lipid. In some embodiments the lipid conjugated to the polymer comprised of at least one neutral lipid, at least one phospholipid, at least one anionic lipid, at least one cationic lipid, at least one cholesterol, at least one cholesterol derivative, or any combination thereof. [0694] In some embodiments, the lipid conjugated to the polymer may be selected from, but is not limited to, at least one of the cationic, non-cationic, or sterol lipids listed previously. [0695] In some embodiments, the at least one PEG-lipid conjugate may be selected from, but is not limited to at least one of Siglec-1L-PEG-DSPE, R)-2,3-bis(octadecyloxy)propyl-1- (methoxypoly(ethyleneglycol)2000)propylcarbamate, PEG-S-DSG, PEG-S-DMG, PEG-PE, PEG-PAA, PEG-OH DSPE C18, PEG-DSPE, PEG-DSG, PEG-DPG, PEG-DOMG, PEG- DMPE Na, PEG-DMPE, PEG-DMG2000, PEG-DMG C14, PEG-DMG 2000, PEG-DMG, PEG-DMA, PEG-Ceramide C16, PEG-C-DOMG, PEG-c-DMOG, PEG-c-DMA, PEG- cDMA, PEGA, PEG750-C-DMA, PEG400, PEG2k-DMG, PEG2k-C11, PEG2000-PE, PEG2000P, PEG2000-DSPE, PEG2000-DOMG, PEG2000-DMG, PEG2000-C-DMA, PEG2000, PEG200, PEG(2k)-DMG, PEG DSPE C18, PEG DMPE C14, PEG DLPE C12, PEG Click DMG C14, PEG Click C12, PEG Click C10, N(Carbonyl-methoxypolyethylenglycol- 2000)-1,2-distearoyl-sn-glycero3-phosphoethanolamine, Myrj52, mPEG-PLA, MPEG-DSPE, mPEG3000-DMPE, MPEG-2000-DSPE, MPEG2000-DSPE, mPEG2000-DPPE, mPEG2000- DMPE, mPEG2000-DMG, mDPPE-PEG2000, 1,2-distearoyl-sn-glycero-3- phosphoethanolamine-PEG2000, HPEG-2K-LIPD, Folate PEG-DSPE, DSPE-PEGMA 500, DSPE-PEGMA, DSPE-PEG6000, DSPE-PEG5000, DSPE-PEG2K-NAG, DSPE-PEG2k, DSPE-PEG2000maleimide, DSPE-PEG2000, DSPE-PEG, DSG-PEGMA, DSG-PEG5000, DPPE-PEG-2K, DPPE-PEG, DPPE-mPEG2000, DPPE-mPEG, DPG-PEGMA, DOPE- PEG2000, DMPE-PEGMA, DMPE-PEG2000, DMPE-Peg, DMPE-mPEG2000, DMG- PEGMA, DMG-PEG2000, DMG-PEG, distearoyl-glycerol-polyethyleneglycol, Cl8PEG750, CI8PEG5000, CI8PEG3000, CI8PEG2000, CI6PEG2000, CI4PEG2000, C18-PEG5000, C18PEG, C16PEG, C16 mPEG (polyethylene glycol) 2000 Ceramide, C14-PEG-DSPE200, C14-PEG2000, C14PEG2000, C14-PEG 2000, C14-PEG, C14PEG, 14:0-PEG2KPE, 1,2- distearoyl-sn-glycero-3-phosphoethanolamine-PEG2000, (R)-2,3-bis(octadecyloxy)propyl-1- (methoxypoly(ethyleneglycol)2000)propylcarbamate, (PEG)-C-DOMG, PEG-C-DMA, and DSPE-PEG-X. [0696] In some embodiments, the LNP comprises a Lipid of the Disclosure, distearoylphosphatidylcholine (DSPC), cholesterol, and 1,2-dimyristoyl-rac-glycero-3- methoxypolyethylene glycol-2000 (DMG-PEG2000). [0697] In some embodiments, the LNP comprises a Lipid of the Disclosure, distearoylphosphatidylcholine (DSPC), cholesterol, and 1,2-dimyristoyl-rac-glycero-3- methoxypolyethylene glycol-2000 (DMG-PEG2000) at a molar ratio of about 48.5:10:40:1.5, respectively. [0698] In some embodiments, the LNP comprises a Lipid of the Disclosure, distearoylphosphatidylcholine (DSPC), cholesterol, and 1,2-distearoyl-sn-glycero-3- phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000) at a molar ratio of about 48.5:10:40:1.5, respectively. [0699] In some embodiments, the LNP comprises a Lipid of the Disclosure, distearoylphosphatidylcholine (DSPC), cholesterol, and 1,2-dimyristoyl-rac-glycero-3- methoxypolyethylene glycol-2000 (DMG-PEG2000) at a molar ratio of about 48.5:10:39:2.5, respectively. [0700] The amounts and ratios of LNP components may be varied by any amount dependent on the desired form, structure, function, cargo, target, or any combination thereof. The amount of each component may be expressed in various embodiments as percent of the total molar mass of all lipid or lipid conjugated components accounted for by the indicated component (mol%), The amount of each component may be expressed in various embodiments as the relative ratio of each component based on molar mass (Molar Ratio). The amount of each component may be expressed in various embodiments as the weight of each component used to formulate the LNP prior to fabrication (mg or equivalent). The amount of each component may be expressed in various embodiments by any other method known in the art. Any formulation given in one representation of component amounts ("units") is expressly meant to encompass any formulation expressed in different units of component amounts, wherein those representations are effectively equivalent when converted into the same units. In some embodiments, "effectively equivalent" means two or more values within about 10% of one another. [0701] In some embodiments, the LNP comprises at least one cationic lipid in an amount of about 0.1 to 100 mol%. In some embodiments, the LNP comprises at least one cationic lipid in an amount of about 20 to 60 mol%. In some embodiments, the LNP comprises at least one cationic lipid in an amount of about 50 to 85 mol%. In some embodiments, the LNP comprises at least one cationic lipid in an amount of less than about 20 mol%. In some embodiments, the LNP comprises at least one cationic lipid in an amount of more than about 60 mol% or about 85 mol%. In some embodiments, the LNP comprises at least one cationic lipid in an amount of about 95 mol% or less. In some embodiments, the LNP comprises a cationic lipid in an amount of less than or equal to about 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, and 5 mol%. In some embodiments, the LNP comprises at least one cationic lipid in an amount of more than or equal to about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, and 95 mol%. In some embodiments, the LNP comprises at least one cationic lipid in an amount from about 20 to 30 mol%, 20 to 35 mol%, 20 to 40 mol%, 20 to 45 mol%, 20 to 50 mol%, 20 to 55 mol%, 20 to 60 mol%, 20 to 65 mol%, 20 to 70 mol%, 20 to 75 mol%, 20 to 80 mol%, 20 to 85 mol%, 20 to 90 mol%, 25 to 35 mol%, 25 to 40 mol%, 25 to 45 mol%, 25 to 50 mol%, 25 to 55 mol%, 25 to 60 mol%, 25 to 65 mol%, 25 to 70 mol%, 25 to 75 mol%, 25 to 80 mol%, 25 to 85 mol%, 25 to 90 mol%, 30 to 40 mol%, 30 to 45 mol%, 30 to 50 mol%, 30 to 55 mol%, 30 to 60 mol%, 30 to 65 mol%, 30 to 70 mol%, 30 to 75 mol%, 30 to 80 mol%, 30 to 85 mol%, 30 to 90 mol%, 35 to 40 mol%, 35 to 45 mol%, 35 to 50 mol%, 35 to 55 mol%, 35 to 60 mol%, 35 to 65 mol%, 35 to 70 mol%, 35 to 75 mol%, 35 to 80 mol%, 35 to 85 mol%, 35 to 90 mol%, 40 to 45 mol%, 40 to 50 mol%, 40 to 55 mol%, 40 to 60 mol%, 40 to 65 mol%, 40 to 70 mol%, 40 to 75 mol%, 40 to 80 mol%, 40 to 85 mol%, 40 to 90 mol%, 45 to 55 mol%, 45 to 60 mol%, 45 to 65 mol%, 45 to 70 mol%, 45 to 75 mol%, 45 to 80 mol%, 45 to 85 mol%, 45 to 90 mol%, 50 to 60 mol%, 50 to 65 mol%, 50 to 70 mol%, 50 to 75 mol%, 50 to 80 mol%, 50 to 85 mol%, 50 to 90 mol%, 55 to 65 mol%, 55 to 70 mol%, 55 to 75 mol%, 55 to 80 mol%, 55 to 85 mol%, 55 to 90 mol%, 60 to 70 mol%, 60 to 75 mol%, 60 to 80 mol%, 60 to 85 mol%, 60 to 90 mol%, 65 to 75 mol%, 65 to 80 mol%, 65 to 85 mol%, 65 to 90 mol%, 70 to 80 mol%, 70 to 85 mol%, 70 to 90 mol%, 75 to 85 mol%, 75 to 90 mol%, 80 to 90 mol% or 85 to 95 mol%. [0702] In some embodiments, the LNP comprises at least one non-cationic lipid in an amount of about 0.1 to 100 mol%. In some embodiments, the LNP comprises at least one non-one cationic lipid in an amount of about 5 to 35 mol%. In some embodiments, the LNP comprises at least one cationic lipid in an amount of about 5 to 25 mol%. In some embodiments, the LNP comprises at least one non-cationic lipid in an amount of less than about 5 mol%. In some embodiments, the LNP comprises at least one non-cationic lipid in an amount of more than about 25 mol% or about 35 mol%. In some embodiments, the LNP comprises at least one non- cationic lipid in an amount of about 95 mol% or less. In some embodiments, the LNP comprises at least one non-cationic lipid in an amount of less than or equal to about 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, and 5 mol%. In some embodiments, the LNP comprises at least one non-cationic lipid in an amount of more than or equal to about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, and 95 mol%. In some embodiments, the LNP comprises at least one non-cationic lipid in an amount from about 5 to 15 mol%, 5 to 25 mol%, 5 to 35 mol%, 5 to 45 mol%, 5 to 55 mol%, 10 to 20 mol%, 10 to 30 mol%, 10 to 40 mol%, 10 to 50 mol%, 15 to 25 mol%, 15 to 35 mol%, 15 to 45 mol%, 20 to 30 mol%, 20 to 40 mol%, 20 to 50 mol%, 25 to 35 mol%, 25 to 45 mol%, 30 to 40 mol%, 30 to 50 mol%, and 35 to 45 mol%. [0703] In some embodiments, the LNP comprises at least one sterol in an amount of about 0.1 to 100 mol%. In some embodiments, the LNP comprises at least one sterol in an amount of about 20 to 45 mol%. In some embodiments, the LNP comprises at least one sterol in an amount of about 25 to 55 mol%. In some embodiments, the LNP comprises at least one sterol in an amount of less than about 20 mol%. In some embodiments, the LNP comprises at least one sterol in an amount of more than about 45 mol% or about 55 mol%. In some embodiments, the LNP comprises at least one sterol in an amount of about 95 mol% or less. In some embodiments, the LNP comprises at least one sterol in an amount of less than or equal to about 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, and 5 mol%. In some embodiments, the LNP comprises at least one sterol in an amount of more than or equal to about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, and 95 mol%. In some embodiments, the LNP comprises at least one sterol in an amount from about 10 to 20 mol%, 10 to 30 mol%, 10 to 40 mol%, 10 to 50 mol%, 10 to 60 mol%, 15 to 25 mol%, 15 to 35 mol%, 15 to 45 mol%, 15 to 55 mol%, 15 to 65 mol%, 20 to 30 mol%, 20 to 40 mol%, 20 to 50 mol%, 20 to 60 mol%, 25 to 35 mol%, 25 to 45 mol%, 25 to 55 mol%, 25 to 65 mol%, 30 to 40 mol%, 30 to 50 mol%, 30 to 60 mol%, 35 to 45 mol%, 35 to 55 mol%, 35 to 65 mol%, 40 to 50 mol%, 40 to 60 mol%, 45 to 55 mol%, 45 to 65 mol%, 50 to 60 mol%, and 55 to 65 mol%. [0704] In some embodiments, the LNP comprises at least one particle-activity-modifying- agent in an amount of about 0.1 to 100 mol%. In some embodiments, the LNP comprises at least one particle-activity-modifying-agent in an amount of about 0.5 to 15 mol%. In some embodiments, the LNP comprises at least one particle-activity-modifying-agent in an amount of about 15 to 40 mol%. In some embodiments, the LNP comprises at least one particle- activity-modifying-agent in an amount of less than about 0.1 mol%. In some embodiments, the LNP comprises at least one particle-activity-modifying-agent in an amount of more than about 15 mol% or about 40 mol%. In some embodiments, the LNP comprises at least one particle- activity-modifying-agent in an amount of about 95 mol% or less. In some embodiments, the LNP comprises at least one particle-activity-modifying-agent in an amount of less than or equal to about 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, and 5 mol%. In some embodiments, the LNP comprises at least one particle-activity-modifying-agent in an amount of more than or equal to about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, and 95 mol%. In some embodiments, the LNP comprises at least one particle- activity-modifying-agent in an amount from about 0.1 to 1 mol%, 0.1 to 2 mol%, 0.1 to 3 mol%, 0.1 to 4 mol%, 0.1 to 5 mol%, 0.1 to 6 mol%, 0.1 to 7 mol%, 0.1 to 8 mol%, 0.1 to 9 mol%, 0.1 to 10 mol%, 0.1 to 15 mol%, 0.1 to 20 mol%, 0.1 to 25 mol%, 1 to 2 mol%, 1 to 3 mol%, 1 to 4 mol%, 1 to 5 mol%, 1 to 6 mol%, 1 to 7 mol%, 1 to 8 mol%, 1 to 9 mol%, 1 to 10 mol%, 1 to 15 mol%, 1 to 20 mol%, 1 to 25 mol%, 2 to 3 mol%, 2 to 4 mol%, 2 to 5 mol%, 2 to 6 mol%, 2 to 7 mol%, 2 to 8 mol%, 2 to 9 mol%, 2 to 10 mol%, 2 to 15 mol%, 2 to 25 mol%, 3 to 4 mol%, 3 to 5 mol%, 3 to 6 mol%, 3 to 7 mol%, 3 to 8 mol%, 3 to 9 mol%, 3 to 10 mol%, 3 to 15 mol%, 3 to 20 mol%, 3 to 25 mol%, 4 to 5 mol%, 4 to 6 mol%, 4 to 7 mol%, 4 to 8 mol%, 4 to 9 mol%, 4 to 10 mol%, 4 to 15 mol%, 4 to 20 mol%, 4 to 25 mol%, 5 to 10 mol%, 5 to 15 mol%, 5 to 20 mol%, 5 to 25 mol%, 10 to 15 mol%, 10 to 20 mol%, 10 to 25 mol%, 15 to 20 mol%, 15 to 25 mol%, and 20 to 25 mol%. [0705] In some embodiments, the LNP is comprised of about 30-60 mol% of at least one cationic lipid, about 0-30 mol% of at least one non-cationic lipid (e.g., a phospholipid), about 18.5-48.5 mol% of at least one sterol (e.g., cholesterol), and about 0-10 mol% of at least one particle-activity-modifying-agent (e.g., a PEGylated lipid). [0706] In some embodiments, the LNP is comprised of about 35-55 mol% of at least one cationic lipid, about 5-25 mol% of at least one non-cationic lipid (e.g., a phospholipid), about 30-40 mol% of at least one sterol (e.g., cholesterol), and about 0-10 mol% of at least one particle-activity-modifying-agent (e.g., a PEGylated lipid). [0707] In some embodiments, the LNP is comprised of about 35-45 mol% of at least one cationic lipid, about 25-35 mol% of at least one non-cationic lipid (e.g., a phospholipid), about 20-30 mol% of at least one sterol (e.g., cholesterol), and about 0-10 mol% of at least one particle-activity-modifying-agent (e.g., a PEGylated lipid). [0708] In some embodiments, the LNP is comprised of about 45-65 mol% of at least one cationic lipid, about 5-10 mol% of at least one non-cationic lipid (e.g., a phospholipid), about 25-40 mol% of at least one sterol (e.g., cholesterol), and about 0.5-10 mol% of at least one particle-activity-modifying-agent (e.g., a PEGylated lipid). [0709] In some embodiments, the LNP is comprised of about 40-60 mol% of at least one cationic lipid, about 5-15 mol% of at least one non-cationic lipid (e.g., a phospholipid), about 35-45 mol% of at least one sterol (e.g., cholesterol), and about 0.5-3 mol% of at least one particle-activity-modifying-agent (e.g., a PEGylated lipid). [0710] In some embodiments, the LNP is comprised of about 30-60 mol% of at least one cationic lipid, about 0-30 mol% of at least one non-cationic lipid (e.g., a phospholipid), about 15-50 mol% of at least one sterol (e.g., cholesterol), and about 0.01-10 mol% of at least one particle-activity-modifying-agent (e.g., a PEGylated lipid). [0711] In some embodiments, the LNP is comprised of about 10-75 mol% of at least one cationic lipid, about 0.5-50 mol% of at least one non-cationic lipid (e.g., a phospholipid), about 5-60 mol% of at least one sterol (e.g., cholesterol), and about 0.1-20 mol% of at least one particle-activity-modifying-agent (e.g., a PEGylated lipid). [0712] In some embodiments, the LNP is comprised of about 50-65 mol% of at least one cationic lipid, about 3-15 mol% of at least one non-cationic lipid (e.g., a phospholipid), about 30-40 mol% of at least one sterol (e.g., cholesterol), and about 0.5-2 mol% of at least one particle-activity-modifying-agent (e.g., a PEGylated lipid). [0713] In some embodiments, the LNP is comprised of about 50-85 mol% of at least one cationic lipid, about 3-15 mol% of at least one non-cationic lipid (e.g., a phospholipid), about 30-40 mol% of at least one sterol (e.g., cholesterol), and about 0.5-2 mol% of at least one particle-activity-modifying-agent (e.g., a PEGylated lipid). [0714] In some embodiments, the LNP is comprised of about 25-75 mol% of at least one cationic lipid, about 0.1-15 mol% of at least one non-cationic lipid (e.g., a phospholipid), about 5-50 mol% of at least one sterol (e.g., cholesterol), and about 0.5-20 mol% of at least one particle-activity-modifying-agent (e.g., a PEGylated lipid). [0715] In some embodiments, the LNP is comprised of about 50-65 mol% of at least one cationic lipid, about 5-10 mol% of at least one non-cationic lipid (e.g., a phospholipid), about 25-35 mol% of at least one sterol (e.g., cholesterol), and about 5-10 mol% of at least one particle-activity-modifying-agent (e.g., a PEGylated lipid). [0716] In some embodiments, the LNP is comprised of about 20-60 mol% of at least one cationic lipid, about 5-25 mol% of at least one non-cationic lipid (e.g., a phospholipid), about 25-55 mol% of at least one sterol (e.g., cholesterol), and about 0.5-15 mol% of at least one particle-activity-modifying-agent (e.g., a PEGylated lipid). [0717] In some embodiments, the LNPs can be characterized by their shape. In some embodiments, the LNPs are essentially spherical. In some embodiments, the LNPs are essentially rod-shaped (i.e., cylindrical). In some embodiments, the LNPs are essentially disk shaped. [0718] In some embodiments, the LNPs can be characterized by their size. In some embodiments, the size of an LNP can be defined as the diameter of its largest circular cross section, referred to herein simply as its diameter. In some embodiments the LNPs may have a diameter between 30 nm to about 150 nm. In some embodiments, the LNP may have diameters ranging between about 40 to 150 nm 50 to 150 nm, 60 to 150 nm, about 70 to 150 nm, or 80 to 150 nm, 90 to 150 nm, 100 to nm, 110 to 150 nm, 120 to 150 nm, 130 to 150 nm, 140 to 150 nm, 30 to 30 to 140 mol%, 40 to 140 mol%, 50 to 140 mol%, 60 to 140 mol%, 70 to 140 mol%, 80 to 140 mol%, 90 to 140 mol%, 100 to 140 mol%, 110 to 140 mol%, 120 to 140 mol%, 130 to 140 mol%, 140 to 140 mol%, 30 to 140 mol%, 40 to 130 mol%, 50 to 130 mol%, 60 to 130 mol%, 70 to 130 mol%, 80 to 130 mol%, 90 to 130 mol%, 100 to 130 mol%, 110 to 130 mol%, 120 to 130 mol%, 30 to 120 mol%, 40 to 120 mol%, 50 to 120 mol%, 60 to 120 mol%, 70 to 120 mol%, 80 to 120 mol%, 90 to 120 mol%, 100 to 120 mol%, 110 to 120 mol%, 30 to 110 mol%, 40 to 110 mol%, 50 to 110 mol%, 60 to 110 mol%, 70 to 110 mol%, 80 to 110 mol%, 90 to 110 mol%, 100 to 110 mol%, 30 to 100 mol%, 40 to 100 mol%, 50 to 100 mol%, 60 to 100 mol%, 70 to 100 mol%, 80 to 100 mol%, 90 to 100 mol%, 30 to 90 mol%, 40 to 90 mol%, 50 to 90 mol%, 60 to 90 mol%, 70 to 90 mol%, 80 to 90 mol%, 30 to 80 mol%, 40 to 80 mol%, 50 to 80 mol%, 60 to 80 mol%, 70 to 80 mol%, 30 to 70 mol%, 40 to 70 mol%, 50 to 70 mol%, 60 to 70 mol%, 30 to 60 mol%, 40 to 60 mol%, 50 to 60 mol%, 30 to 50 mol%, 40 to 50 mol%, and 30 to 40 mol%. [0719] In some embodiments, a population of LNPs, such as those resulting from the same formulation, may be characterized by measuring the uniformity of size, shape, or mass of the particles in the population. Uniformity may be expressed in some embodiments as the polydispersity index (PI) of the population. In some embodiments uniformity may be expressed in some embodiments as the disparity (Đ) of the population. The terms "polydispersity index" and "disparity" are understood herein to be equivalent and may be used interchangeably. In some embodiments, a population of LNPs resulting from a given formulation will have a PI of between about 0.1 and 1. In some embodiments, a population of LNPs resulting from a giving formulation will have a PI of less than about 1, less than about 0.5, less than about 0.4, less than about 0.3, less than about 0.2, less than about 0.1. In some embodiments, a population of LNPs resulting from a given formulation will have a PI of between about 0.1 to 1, 0.1 to 0.8, 0.1 to 0.6, 0.1 to 0.4, 0.1 to 0.2, 0.2 to 1, 0.2 to 0.8, 0.2 to 0.6, 0.2 to 0.4, 0.4 to 1, 0.4 to 0.8, 0.4 to 0.6, 0.6 to 1, 0.6 to 0.8, and 0.8 to 1. [0720] In some embodiments, the LNP may fully or partially encapsulate a cargo, such as the originator constructs and benchmark constructs of the present disclosure. In some embodiments, essentially 0% of the cargo present in the final formulation is exposed to the environment outside of the LNP (i.e., the cargo is fully encapsulated. In some embodiments, the cargo is associated with the LNP but is at least partially exposed to the environment outside of the LNP. In some embodiments, the LNP may be characterized by the % of the cargo not exposed to the environment outside of the LNP, e.g., the encapsulation efficiency. For the sake of clarity, an encapsulation efficiency of about 100% refers to an LNP formulation where essentially all the cargo is fully encapsulated by the LNP, while an encapsulation rate of about 0% refers to an LNP where essential none of the cargo is encapsulated in the LNP, such as with an LNP where the cargo is bound to the external surface of the LNP. On some embodiments, an LNP may have an encapsulation efficiency of less than about 100%, less than about 95%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15% less than about 10%, or less than 5%. In some embodiments, an LNP may have an encapsulation efficiency of between about 90 to 100%, 80 to 100%, 70 to 100%, 60 to 100%, 50 to 100%, 40 to 100%, 30 to 100%, 20 to 100%, 10 to 100%, 80 to 90%, 70 to 90%, 60 to 90%, 50 to 90%, 40 to 90%, 30 to 90%, 20 to 90%, 10 to 90%, 70 to 80%, 60 to 80%, 50 to 80%, 40 to 80%, 30 to 80%, 20 to 80%, 10 to 80%, 60 to 70%, 50 to 70%, 40 to 70%, 30 to 70%, 20 to 70%, 10 to 70%, 40 to 50%, 30 to 50%, 20 to 50%, 10 to 50%, 30 to 40%, 20 to 40%, 10 to 40%, 20 to 30%, 10 to 30%, and 10 to 20%. [0721] In some embodiments, a LNP may include at least one identifier moiety as shown in FIG.5. Non-limiting examples of an identifier moiety include glycans, antibodies, peptides, small molecules, and any combination thereof. In some embodiments, the at least one targeting agent may be incorporated into the lipid membrane of the lipid-based nanoparticle. In some embodiments, the at least one targeting agent may be presented on the external surface of the nanoparticle. In some embodiments, the at least one targeting agent may be conjugated to a lipid-component of the nanoparticle. In some embodiments, the at least one targeting agent may be conjugated to a polymer component of the nanoparticle. In some embodiments, the at least one targeting agent may be anchored to the nanoparticle via hydrophobic ad hydrophilic interactions among the at least one targeting agent, the nanoparticle membrane, and the aqueous environments inside or outside the nanoparticle. In some embodiments, the at least one targeting agent is conjugated to a peptide/protein component of the nanoparticle membrane. In some embodiments, the at least one targeting agent is conjugated to a suitable linker moiety which is conjugated to a component of the nanoparticle membrane. In some embodiments, any combination of forces and bonds can result in the targeting agent being associated with the nanoparticle. [0722] The LNPs described herein may be formed using techniques known in the art. As a non- limiting example, an organic solution containing the lipids is mixed together with an acidic aqueous solution containing the originator construct or benchmark construct in a microfluidic channel resulting in the formation of targeting system (delivery vehicle and the benchmark construct). [0723] In some embodiments, each LNP formulation includes a benchmark construct having a uniquely identifiable nucleotide identifier sequence (e.g., barcode). The unique identifier sequence provides the ability to identify the specific LNP which produces the desired result. The LNP formulation may also differ in the LNP-forming composition used to generate the LNP. For example, the LNP-forming compositions can be varied in the molar amount and/or structure of the ionizable lipid, the molar amount and/or structure of the helper lipid, the molar amount/or structure of PEG, and/or the molar amount of cholesterol. Additionally, or alternatively, the LNP formulation may comprise benchmark constructs which differ in the coding sequence for the biologically active molecule. Additionally, or alternatively, the LNP formulation may comprise benchmark constructs which differ in the modifications made to the nucleic acid sequence. [0724] In some embodiments, the lipid compositions described according to the respective molar ratios of the component lipids in the formulation. As a non-limiting example, the mol-% of the ionizable lipid may be from about 10 mol-% to about 80 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 20 mol-% to about 70 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 30 mol-% to about 60 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 35 mol-% to about 55 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 40 mol-% to about 50 mol-%. As a non-limiting example, the ionizable lipid mol-% of the transfer vehicle batch will be ±30%, ±25%, ±20%, ±15%, ±10%, ±5%, or ±2.5% of the target mol-%. In some embodiments, transfer vehicle variability between lots will be less than 15%, less than 10% or less than 5%. [0725] In some embodiments, the mol-% of the helper lipid may be from about 1 mol-% to about 50 mol-%. In some embodiments, the mol-% of the helper lipid may be from about 2 mol-% to about 45 mol-%. In some embodiments, the mol-% of the helper lipid may be from about 3 mol-% to about 40 mol-%. In some embodiments, the mol-% of the helper lipid may be from about 4 mol-% to about 35 mol-%. In some embodiments, the mol-% of the helper lipid may be from about 5 mol-% to about 30 mol-%. In some embodiments, the mol-% of the helper lipid may be from about 10 mol-% to about 20 mol-%. In some embodiments, the helper lipid mol-% of the transfer vehicle batch will be ±30%, ±25%, ±20%, ±15%, ±10%, ±5%, or ±2.5% of the target mol-%. [0726] In some embodiments, the mol-% of the structural lipid may be from about 10 mol-% to about 80 mol-%. In some embodiments, the mol-% of the structural lipid may be from about 20 mol-% to about 70 mol-%. In some embodiments, the mol-% of the structural lipid may be from about 30 mol-% to about 60 mol-%. In some embodiments, the mol-% of the structural lipid may be from about 35 mol-% to about 55 mol-%. In some embodiments, the mol-% of the structural lipid may be from about 40 mol-% to about 50 mol-%. In some embodiments, the structural lipid mol-% of the transfer vehicle batch will be ±30%, ±25%, ±20%, ±15%, ±10%, ±5%, or ±2.5% of the target mol-%. [0727] In some embodiments, the mol-% of the PEG modified lipid may be from about 0.1 mol-% to about 10 mol-%. In some embodiments, the mol-% of the PEG modified lipid may be from about 0.2 mol-% to about 5 mol-%. In some embodiments, the mol-% of the PEG modified lipid may be from about 0.5 mol-% to about 3 mol-%. In some embodiments, the mol-% of the PEG modified lipid may be from about 1 mol-% to about 2 mol-%. In some embodiments, the mol-% of the PEG modified lipid may be about 1.5 mol-%. In some embodiments, the PEG modified lipid mol-% of the transfer vehicle batch will be ±30%, ±25%, ±20%, ±15%, ±10%, ±5%, or ±2.5% of the target mol-%. [0728] In some embodiments, the delivery vehicle may be any of the lipid nanoparticles described in WO2021113777, the contents of which are herein incorporated by reference in their entirety. [0729] In some embodiments, the delivery vehicle is a lipid nanoparticle which comprises any of the ionizable lipids (e.g., amine lipids), PEG lipids, non-cationic (helper) lipids, or structural lipids in WO2021113777, the contents of which are herein incorporated by reference in their entirety. [0730] In some embodiments, a lipid nanoparticle formulation may be prepared by the methods described in International Publication Nos. WO2011127255 or W02008103276, the contents of each of which is herein incorporated by reference in their entirety. In some embodiments, lipid nanoparticle formulations may be as described in International Publication No. W02019131770, the contents of which is herein incorporated by reference in its entirety. [0731] In some embodiments, a lipid nanoparticle formulation may be prepared by the methods described in International Publication No. WO2020237227, the contents of each of which is herein incorporated by reference in their entirety. In some embodiments, lipid nanoparticle formulations may be as described in International Publication No. WO2020237227, the contents of which is herein incorporated by reference in its entirety. Non-Lipid Nanoparticle [0732] In some embodiments, the nanoparticle is a non-lipid-based nanoparticle. Non-lipid- based nanoparticles include, but are not limited to, silicon-based nanoparticles (i.e., porous silicon nanoparticles), gold nanoparticles, polypeptide-based nanoparticles, nucleotide-based nanoparticles, and carbon-based nanoparticle. Exosomes [0733] In some embodiments, the delivery vehicle comprises at least one exosome. As used herein, "exosomes" refer to small membrane bound vesicles with an endocytic origin. Without wishing to be bound by theory, exosomes are generally released into an extracellular environment from host/progenitor cells post fusion of multivesicular bodies the cellular plasma membrane. As such, exosomes will tend to include components of the progenitor membrane in addition to designed components and cargos. Exosome membranes are generally lamellar, composed of a bilayer of lipids, with an aqueous inter-nanoparticle space. [0734] In some embodiments, an exosome may include at least one identifier moiety as shown in FIG.5. Non-limiting examples of an identifier moiety include glycans, antibodies, peptides, small molecules, and any combination thereof. Liposomes [0735] In some embodiments, the delivery vehicles comprise of at least one liposome. As used herein, "liposomes" are small vesicles comprised of at least one lipid bilayer membrane surrounding an aqueous inner-nanoparticle space that is generally not derived from a progenitor/host cell. Liposomes can be (large) multilamellar vesicle (MLV), potentially hundreds of nanometers in diameter comprising a series of concentric bilayers separated by narrow aqueous spaces, small unicellular vesicle (SUV), potentially smaller than 50 nm in diameter, and a large unilamellar vesicle (LUV), potentially between 50 and 500 nm in diameter. In some embodiments, liposomes may be comprised of any or all the same components and same component amounts as a lipid nanoparticle, differing principally in their method of manufacture. Micelles [0736] In some embodiments, the delivery vehicles comprise of at least one micelle. As used herein, "micelles" refer to small particles which do not have an aqueous intra-particle space. Without wishing to be bound by theory, the intra-particle space of micelles is occupied by the hydrophobic tails of the lipids comprising the micelle membrane and possible associated cargo, rather than any additional lipid-head groups. In some embodiments, micelles may be comprised of any or all the same components as a lipid-nanoparticle, differing principally in their method of manufacture. [0737] In some embodiments, a micelle may include at least one identifier moiety as shown in FIG.5. Non-limiting examples of an identifier moiety include glycans, antibodies, peptides, small molecules, and any combination thereof. Viral particle [0738] In some embodiments, the delivery vehicle comprises at least one virus like particle. As used herein, "virus like particles" refer to a vesicle predominantly of a protein capsid, sheath, shell, or coat (all used interchangeably herein) derived from a virus which can be loaded with a cargo moiety. In general, virus like particle are non-infection and may be synthesized using cellular machinery to express viral capsid protein sequences, which then self-assemble and incorporate the associated cargo moiety, though it is possible to form virus like particles by providing the capsid and cargo components without expression related cellular machinery and allowing them to self-assemble. [0739] In some embodiments, the virus like particle may be derived from at least one of species of virus such as, but not limited to, Parvoviridae, Retroviridae, Flaviviridae, Paramyxoviridae, and bacteriophages. In some embodiments, the virus like particle may be derived from an adeno-associated virus, HIV, Hepatitis C virus, HPV, or any combination thereof. [0740] In some embodiments, the virus like particle is an AAV particle and the AAV particle may include at least one identifier moiety as shown in FIG.5. Non-limiting examples of an identifier moiety include glycans, antibodies, peptides, small molecules, and any combination thereof. Polymeric delivery technology [0741] In some embodiments, the delivery vehicle may comprise at least one polymeric delivery agent. As used herein, "polymeric delivery agents" refer to non-aggregating delivery agents comprised of soluble polymers conjugated to cargo moieties via various linkage groups. In some embodiments, polymeric delivery agents may comprise any of the polymers described herein. Tracking Systems [0742] The tropism discovery platform disclosed herein may utilize a variety of tracking systems which include identifier sequences and moieties (also referred to as a "barcode") in order to allow qualification of the delivery vehicles and/or the benchmark constructs, cargo and payloads post-administration. [0743] In some embodiments, the tracking system is a single identifier sequence or moiety. The identifier sequence or moiety may be located in the delivery vehicle, benchmark construct, cargo or payload region, 5' UTR, 3'UTR, promoter region or tailing region. As a non-limiting example, the identifier sequence or moiety is located in or on the delivery vehicle. As a non- limiting example, the identifier sequence or moiety is located in or on the benchmark construct. As a non-limiting example, the identifier sequence or moiety is located in or on the 5' UTR. As a non-limiting example, the identifier sequence or moiety is located in or on the 3' UTR. As a non-limiting example, the identifier sequence or moiety is located in or on the promoter region. As a non-limiting example, the identifier sequence or moiety is located in or on the payload region. As a non-limiting example, the identifier sequence or moiety is located in or on the tailing region. [0744] In some embodiments, the tracking system is a set of identifier sequences or moieties with a first identifier sequence or moiety for the delivery vehicle and a second identifier sequence or moiety for the benchmark construct, cargo and payload. The first and second identifier sequence or moiety may be the same or different. If there are additional benchmark constructs, cargos and payloads in the delivery vehicle then each benchmark constructs, cargo and payloads may have its own identifier sequence or moiety or it may be the same at the second identifier sequence or moiety. [0745] In some embodiments, the tropism discovery platform is comprised of multiple tracking systems, wherein each tracking system allows for detecting the delivery vehicle and/or benchmark constructs, cargo and payloads at different levels of resolution. [0746] In some embodiments, the tracking systems comprises at least one barcode sequence. As used herein, a "barcode" or "barcode sequence" is any sequence which can be detected using methods known in the art and is distinct from the sequences in the cell, tissue, organ and/or organism or any sequences being administered. The barcode sequence may be included in or attached to the delivery vehicle and/or in the benchmark construct, cargo and payload. As a non-limiting example, the delivery vehicle comprises the barcode sequence. As a non-limiting example, the cargo or payload comprises the barcode sequence. As a non-limiting example, the benchmark construct comprises the barcode sequence. [0747] In some embodiments, the location of the identifier sequence or moiety in the targeting system is random. As a non-limiting example, the identifier sequence or moiety is in the delivery vehicle. As a non-limiting example, the identifier sequence or moiety is in the delivery vehicle. As a non-limiting example, the identifier sequence or moiety is in the benchmark construct. As a non-limiting example, the identifier sequence or moiety is in the cargo or payload. As a non-limiting example, the identifier sequence or moiety is in the delivery vehicle and the benchmark construct. As a non-limiting example, the identifier sequence or moiety is in the delivery vehicle and the cargo or payload. As a non-limiting example, the identifier sequence or moiety is in the benchmark construct and the cargo or payload. As a non-limiting example, the identifier sequence or moiety is in the delivery vehicle, benchmark construct, and the cargo or payload. [0748] In some embodiments, the location of the identifier sequence or moiety in the targeting system is pre-determined. As a non-limiting example, the identifier sequence or moiety is in the delivery vehicle. As a non-limiting example, the identifier sequence or moiety is in the delivery vehicle. As a non-limiting example, the identifier sequence or moiety is in the benchmark construct. As a non-limiting example, the identifier sequence or moiety is in the cargo or payload. As a non-limiting example, the identifier sequence or moiety is in the delivery vehicle and the benchmark construct. As a non-limiting example, the identifier sequence or moiety is in the delivery vehicle and the cargo or payload. As a non-limiting example, the identifier sequence or moiety is in the benchmark construct and the cargo or payload. As a non- limiting example, the identifier sequence or moiety is in the delivery vehicle, benchmark construct, and the cargo or payload. [0749] In some embodiments, the location of the identifier sequence or moiety in the targeting system is inverted. As a non-limiting example, the identifier sequence or moiety is in the delivery vehicle. As a non-limiting example, the identifier sequence or moiety is in the delivery vehicle. As a non-limiting example, the identifier sequence or moiety is in the benchmark construct. As a non-limiting example, the identifier sequence or moiety is in the cargo or payload. As a non-limiting example, the identifier sequence or moiety is in the delivery vehicle and the benchmark construct. As a non-limiting example, the identifier sequence or moiety is in the delivery vehicle and the cargo or payload. As a non-limiting example, the identifier sequence or moiety is in the benchmark construct and the cargo or payload. As a non-limiting example, the identifier sequence or moiety is in the delivery vehicle, benchmark construct, and the cargo or payload. [0750] In some embodiments, the identifier sequence is a randomly generated sequences which serve to avoid duplication during deep sequencing. In some embodiments, the identifier sequence is a repeating sequence of nucleotides or amino acids. In some embodiments, the identifier sequence is a fragment of a larger sequence such as, but not limited to, a cargo or payload. The identifier sequence may be designed to any length available using synthesis technology (See Clement et al., AmpUMI: design and analysis of unique molecular identifiers for deep amplicon sequencing, Bioinformatics, Volume 34, Issue 13, 01 July 2018, Pages i202- i210; the contents of which is herein incorporated herein by reference in its entirety). [0751] In some embodiments, the identifier sequence has a length between 2 and 1000 nucleotides. For example, the identifier sequence may have a length of 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000 or more than 1000 nucleotides. The identifier sequence may have a length between 2-5, 2-10, 2-15, 2-20, 2-30, 2-50, 2-70, 2-90, 2-100, 2-250, 2-300, 2-350, 2-400, 2-450, 2-500, 2-550, 2-600, 2-650, 2-700, 2-750, 2-800, 2-850, 2-900, 2-950, 2-1000, 5-10, 5-15, 5-20, 5-30, 5-50, 5-70, 5-90, 5-100, 5-250, 5-300, 5-350, 5-400, 5-450, 5-500, 5-550, 5-600, 5-650, 5-700, 5-750, 5-800, 5-850, 5-900, 5-950, 5-1000, 10-30, 10-50, 10-70, 10-90, 10-100, 10-250, 10- 300, 10-350, 10-400, 10-450, 10-500, 10-550, 10-600, 10-650, 10-700, 10-750, 10-800, 10- 850, 10-900, 10-950, 10-1000, 20-30, 20-50, 20-70, 20-90, 20-100, 20-250, 20-300, 20-350, 20-400, 20-450, 20-500, 20-550, 20-600, 20-650, 20-700, 20-750, 20-800, 20-850, 20-900, 20- 950, 20-1000, 30-50, 30-70, 30-90, 30-100, 30-250, 30-300, 30-350, 30-400, 30-450, 30-500, 30-550, 30-600, 30-650, 30-700, 30-750, 30-800, 30-850, 30-900, 30-950, 30-1000, 40-50, 40- 70, 40-90, 40-100, 40-250, 40-300, 40-350, 40-400, 40-450, 40-500, 40-550, 40-600, 40-650, 40-700, 40-750, 40-800, 40-850, 40-900, 40-950, 40-1000, 50-70, 50-90, 50-100, 50-250, 50- 300, 50-350, 50-400, 50-450, 50-500, 50-550, 50-600, 50-650, 50-700, 50-750, 50-800, 50- 850, 50-900, 50-950, 50-1000, 60-70, 60-90, 60-100, 60-250, 60-300, 60-350, 60-400, 60-450, 60-500, 60-550, 60-600, 60-650, 60-700, 60-750, 60-800, 60-850, 60-900, 60-950, 60-1000, 70-90, 70-100, 70-250, 70-300, 70-350, 70-400, 70-450, 70-500, 70-550, 70-600, 70-650, 70- 700, 70-750, 70-800, 70-850, 70-900, 70-950, 70-1000, 80-90, 80-100, 80-250, 80-300, 80- 350, 80-400, 80-450, 80-500, 80-550, 80-600, 80-650, 80-700, 80-750, 80-800, 80-850, 80- 900, 80-950, 80-1000, 90-100, 90-250, 90-300, 90-350, 90-400, 90-450, 90-500, 90-550, 90- 600, 90-650, 90-700, 90-750, 90-800, 90-850, 90-900, 90-950, 90-1000, 100-250, 100-300, 100-350, 100-400, 100-450, 100-500, 100-550, 100-600, 100-650, 100-700, 100-750, 100-800, 100-850, 100-900, 100-950, 100-1000, 150-250, 150-300, 150-350, 150-400, 150-450, 150- 500, 150-550, 150-600, 150-650, 150-700, 150-750, 150-800, 150-850, 150-900, 150-950, 150-1000, 200-250, 200-300, 200-350, 200-400, 200-450, 200-500, 200-550, 200-600, 200- 650, 200-700, 200-750, 200-800, 200-850, 200-900, 200-950, 200-1000, 250-300, 250-350, 250-400, 250-450, 250-500, 250-550, 250-600, 250-650, 250-700, 250-750, 250-800, 250-850, 250-900, 250-950, 250-1000, 300-350, 300-400, 300-450, 300-500, 300-550, 300-600, 300- 650, 300-700, 300-750, 300-800, 300-850, 300-900, 300-950, 300-1000, 350-400, 350-450, 350-500, 350-550, 350-600, 350-650, 350-700, 350-750, 350-800, 350-850, 350-900, 350-950, 350-1000, 400-450, 400-500, 400-550, 400-600, 400-650, 400-700, 400-750, 400-800, 400- 850, 400-900, 400-950, 400-1000, 450-500, 450-550, 450-600, 450-650, 450-700, 450-750, 450-800, 450-850, 450-900, 450-950, 450-1000, 500-550, 500-600, 500-650, 500-700, 500- 750, 500-800, 500-850, 500-900, 500-950, 500-1000, 550-600, 550-650, 550-700, 550-750, 550-800, 550-850, 550-900, 550-950, 550-1000, 600-650, 600-700, 600-750, 600-800, 600- 850, 600-900, 600-950, 600-1000, 650-700, 650-750, 650-800, 650-850, 650-900, 650-950, 650-1000, 700-750, 700-800, 700-850, 700-900, 700-950, 700-1000, 750-800, 750-850, 750- 900, 750-950, 750-1000, 800-850, 800-900, 800-950, 800-1000, 850-900, 850-950, 850-1000, 900-950, 900-1000, 950-1000 or over 1000 nucleotides. [0752] In some embodiments, the identifier sequence or moiety may produce a signal that is detectable immediately after administration. In some embodiments, the identifier sequence or moiety may produce a signal that is detectable for an indefinite amount of time after administration. In some embodiments, the identifier sequence or moiety may produce a signal that is detectable for more than 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days post administration. In some embodiments, the identifier sequence or moiety may produce a signal that is detectable for about 1 to 24 hours. As a non-limiting example, the signal may be detectable for about 1 to 6, 1 to 12, 1 to 18, 6 to 12, 6 to 18, 6 to 24, or 18 to 24 hours, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. In some embodiments, the identifier sequence or moiety may produce a signal that is detectable for about 1-60 minutes such as, but not limited to, 1-5, 1-10, 1-20, 1-30, 1-40, 1-50, 10-20, 10-30, 10-40, 10-50, 10-60, 20-30, 20-40, 20-50, 20-60, 30-40, 30-50, 30-60, 40-50, 40-60, or 50-60 minutes, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 minutes. In some embodiments, the identifier sequence or moiety may produce a signal that is detectable for less than 1 minute post administration. [0753] In some embodiments, the identifier sequence or moiety may produce a signal that is detectable from outside the body of a subject. In some embodiments, the identifier sequence or moiety may produce a signal that is detectable from via non-invasive imagery techniques, for example from outside a subject's organs or tissues but within the subject's body. In some embodiments, the identifier sequence or moiety may produce a signal that is detectable on a macroscopic level. In some embodiments, the identifier sequence or moiety may produce a signal that is detectable on the microscopic level. In some embodiments, the identifier sequence or moiety may produce a signal that is detectable on the nanoscopic level. In some embodiments, the identifier sequence or moiety may produce a signal that is only detectable after target cells are harvested and assayed, for non-limiting example via mass spectrometer, electrophoresis, flow cytometry, or deep sequencing. [0754] In some embodiments, the delivery vehicle comprises or is operably linked to an identifier moiety. [0755] In some embodiments, the delivery vehicle comprises or is operably linked to an identifier moiety that binds to an immune cell antigen. As a non-limiting example, the immune cell antigen may be a T cell antigen such as CD2, CD3, CD5, CD7, CD8, CD4, beta 7 integrin, beta 2 integrin, and C1q. As a non-limiting example, the immune cell antigen may be a NK cell, an NKT cell, a macrophage or a neutrophil. As a non-limiting example, the immune cell antigen may be a macrophage antigen such as mannose receptor, CD206 and C1q. [0756] In some embodiments, the delivery vehicle comprises or is operably linked to an identifier moiety which is a small molecule that binds to an ectoenzyme on an immune cell. The ectoenzyme may be, but is not limited to, CD38, CD73, adenosine 2a receptor and adenosine 2b receptor. [0757] In some embodiments, the delivery vehicle comprises or is operably linked to an identifier moiety which is a small molecule such as, but not limited to, mannose, lectin, acivicin, biotin, or digoxigenin. [0758] In some embodiments, the delivery vehicle comprises or is operably linked to an identifier moiety which is a single chain Fv (scFv) fragment, nanobody, peptide, peptide-based macrocycle, minibody, small molecule ligand (e.g., folate, arginylglycylaspartic acid (RGD), or phenol-soluble modulin alpha 1 peptide (PSMA1)), heavy chain variable region, light chain variable region or fragment thereof. Tracking System: Fluorescence [0759] In some embodiments, the at least one tracking system comprises an identifier sequence or moieties that is detectable by florescence. [0760] In some embodiments, florescence is achieved via the inclusion of at least one fluorescent dye in the delivery vehicle. In some embodiments, the at least one fluorescent dye may be selected from, but is not limited to, fluorescein, TAMRA (carboxytetramethylrhodamine), Cy dyes, Texas red, HEX, JOE, Oregon green, rhodamine 6 G, coumarin, pyrene, and DiOC6 (3,3′-dihexyloxacarbocyanine iodide). [0761] In some embodiments, florescence is achieved via the inclusion of at least one fluorescent protein in the, or associated with, the delivery vehicle. In some embodiments, at least one fluorescent protein is encoded in the benchmark construct or the benchmark construct comprises the fluorescent protein. Non-limiting examples of fluorescent protein include Green Fluorescent Protein (GFP), Yellow Fluorescent Protein (YFP), Red Fluorescent Protein (RFP), Sirius, excitable blue fluorescent protein (EBFP2), cyan fluorescent protein (CFP), Cerulean, excitable green fluorescent protein (EGFP), excitable yellow fluorescent protein (EYFP), mOrange, mCherry, mPlum, NIR, iRFP, EosFP, PamCherry, Dronpa, Dreiklang, asFP595, mMaple, mGeo, mEos2, Dendra2, psCFP2, and 2,3,5,6-tetracarbazole-4-cyano-pyridine (CPy). [0762] In some embodiments, florescence is achieved via the inclusion of at least one fluorescent nanoparticle associated with the delivery vehicle or the benchmark construct. In some embodiments, the fluorescent nanoparticle may be, but is not limited to, carbon dots, graphene quantum dots, gold nanorods, polymer-based nanoparticles, aggregation-induced emission dots, Conjugated Polymer nanoparticles (CP-dots), Gold nanospheres, Gold nano shells, Gold nanocages, and AIE pheromone. [0763] In some embodiments, florescence is achieved via inclusion of at least one fluorescent lipid associated with or included in the delivery vehicle. In some embodiments, the fluorescent lipid may be, but is not limited to, DiR, DiD, DiO, and DiI, other members of the Di series of phospholipids, Bodipy, and FL-Sphingomyelin. [0764] In some embodiments, florescence is achieved via the inclusion of at least one luciferase in or associated with the delivery vehicle. In some embodiments, at least one luciferase protein is encoded in the benchmark construct or the benchmark construct comprises the luciferase. Non-limiting examples of the types of luciferase which may be used include Renilla luciferase, Gaussia luciferase, Nanoluc luciferase, Firefly luciferase, and Click Beetle luciferases. [0765] In some embodiments, florescence is achieved via inclusion of β-galactosidase (β-gal) associated with or included in the delivery vehicle. In some embodiments, at least one β- galactosidase (β-gal) protein is encoded in the benchmark construct or the benchmark construct comprises β-galactosidase (β-gal). [0766] In some embodiments, florescence is achieved via inclusion of at least one quencher molecule associated with or included in the delivery vehicle. In some embodiments, florescence is achieved via inclusion of at least one quencher molecule associated with or encoded by the benchmark construct. Non-limiting examples of quencher molecules include dimethylaminophenylazobenzoic acid (DABCYL), QSY 7, Cu(II) ion, Dabcyl, QSY 35, BHQ- 0, Eclipse, BHQ-1, QSY 9, BHQ-2, ElleQuencher, Iowa Black, QSY 21, and BHQ-3. Tracking System: Fluorophores and Radioactive Phosphates [0767] In some embodiments, the at least one tracking system comprises an identifier sequence or moieties that is a fluorophore or radioactive phosphate. [0768] In some embodiments, the at least one tracking system comprises the inclusion of at least one fluorophore associated with or included in the delivery vehicle. In some embodiments, the at least one tracking system comprises the inclusion of at least one fluorophore associated with, encoded in or included in the benchmark construct. Non-limiting examples of fluorophores includes quantum dot and organic small molecule. [0769] In some embodiments, the at least one tracking system comprises the inclusion of at least one quantum dot associated with or included in the delivery vehicle. In some embodiments, the at least one tracking system comprises the inclusion of at least one quantum dot associated with, encoded in or included in the benchmark construct. Non-limiting examples of quantum dots include CdSe/ZnS, CdTe/ZnS, CdTe/CdSe, CdSe/ZnTe, CdSe/CdTe/ZnSe, nAs/ZnSe, InAs/CdSe, InAs/InP, Cu:InP/ZnSe, InAsxP1–x/InP/ZnSe, CdS/CdSe, ZnSe/CdSe, ZnSe/InP/ZnS, ZnSe/InP/ZnS, CdTe/ZnSe, QD585, and QD655. [0770] In some embodiments, the at least one tracking system comprises the inclusion of at least one organic small molecule associated with or included in the delivery vehicle. In some embodiments, the at least one tracking system comprises the inclusion of at least one organic small molecule associated with, encoded in or included in the benchmark construct. Non- limiting examples of organic small molecules include classes of Coumarins, Naphthalimides, Fluoresceins and rhodamines derivatives, BODIPY, Cyanines, xanthenes, oxazines, Oligothiophenes, and Phthalocyanine derivatives (PcDer). In some embodiments, the at least one organic small molecule may be selected from, but is not limited to, 7-dialkyl-amino-4- trifluoromethyl coumarin, rhodamine B, Coumarin 314, Lucifer Yellow CH, florescein, rhodamine 123, BODIPY FL NHS ester, Cy5, Rhodamine 6G, Silicon-rhodamine (SiR), Cy3, Cy5.5, Cy7, Cy2, ATTO655, ATTO680, ATTO700, Nitrobenzoxadiazole (NBD), 1,6- diphenyl-1,3,5-hexatriene (DPH), ABBERIOR™, ALEXA FLUOR™, ATTO™, DYLIGHT FLUOR™, ALEXA FLUOR 647™, and TOPFLUOR™. [0771] In some embodiments, the at least one tracking system comprises the inclusion of at least one imaging contrast agent associated with or included in the delivery vehicle. In some embodiments, the at least one tracking system comprises the inclusion of at least one imaging contrast agent associated with, encoded in or included in the benchmark construct. Non- limiting examples of imaging contrast agents include gadolinium-based small molecules, gadolinium-encapsulated liposomes, manganese-based small molecules, and iron oxide nanoparticles. [0772] In some embodiments, the at least one tracking system comprises the inclusion of at least one radiolabel associated with or included in the delivery vehicle. In some embodiments, the at least one tracking system comprises the inclusion of at least one radiolabel associated with, encoded in or included in the benchmark construct. Non-limiting examples of radiolabels include 111 In, 99m Tc, 13 N, 68 Ga, 18 F, 64 Cu, 86 Y, 76 Br, 89 Zr, 72 As, 124 I, 74 As, fluorine-18, gallium- 68, nitrogen-13, copper-64, bromine-76, iodine-125, arsenic-74, carbon-11, iodine-131, 153 Sm, 177 Lu, 186 Re, 188 Re, 198 Au, and 225 Ac. [0773] In some embodiments, the at least one tracking system comprises the inclusion of at least one biotin associated with or included in the delivery vehicle. [0774] In some embodiments, the at least one tracking system comprises the inclusion of at least one digoxygenin associated with or included in the delivery vehicle. [0775] In some embodiments, the at least one tracking system comprises the inclusion of at least one dinitrophenyl (DNP) associated with or included in the delivery vehicle. [0776] In some embodiments, the at least one tracking system comprises the inclusion of at least one Fluorescein associated with or included in the delivery vehicle. [0777] In some embodiments, the at least one tracking system comprises the inclusion of at least one fucose associated with or included in the delivery vehicle. [0778] In some embodiments, the at least one tracking system comprises the inclusion of at least one amine associated with or included in the delivery vehicle. [0779] In some embodiments, the at least one tracking system comprises the inclusion of at least one Texas Red® associated with or included in the delivery vehicle. [0780] In some embodiments, the at least one tracking system comprises the inclusion of at least one biotin associated with, encoded in or included in the benchmark construct. [0781] In some embodiments, the at least one tracking system comprises the inclusion of at least one digoxygenin associated with, encoded in or included in the benchmark construct. [0782] In some embodiments, the at least one tracking system comprises the inclusion of at least one dinitrophenyl (DNP) associated with, encoded in or included in the benchmark construct. [0783] In some embodiments, the at least one tracking system comprises the inclusion of at least one Fluorescein associated with, encoded in or included in the benchmark construct. [0784] In some embodiments, the at least one tracking system comprises the inclusion of at least one fucose associated with, encoded in or included in the benchmark construct. [0785] In some embodiments, the at least one tracking system comprises the inclusion of at least one amine associated with, encoded in or included in the benchmark construct. [0786] In some embodiments, the at least one tracking system comprises the inclusion of at least one Texas Red® associated with, encoded in or included in the benchmark construct. [0787] In some embodiments, the at least one tracking system comprises the inclusion of at least one reporter sequence or protein associated with or included in the delivery vehicle. In some embodiments, the at least one tracking system comprises the inclusion of at least one reporter sequence or protein associated with, encoded in or included in the benchmark construct. Non-limiting examples of reporter sequence or protein include eGFP, luciferase, gene editor (e.g. cas9 edit, DNA readout), ox-40, beta6 integrin, CD45, a surface marker with a HA tag, flag tag with or without a TEV protease site, or any combination thereof. [0788] In some embodiments, the at least one tracking system comprises the inclusion of at least one functional sequence or protein associated with or included in the delivery vehicle. In some embodiments, the at least one tracking system comprises the inclusion of at least one functional sequence or protein associated with, encoded in or included in the benchmark construct. Non-limiting examples of functional sequence or protein include fluorescent protein, a surface protein, Cre-Recombinase, CRISPR/CAS system, surface protein with an epitope tag (e.g., HA, FLAG, etc.) or any combination thereof [0789] In some embodiments, the at least one tracking system comprises the inclusion of at least one functional sequence or protein that comprises a protease cleavage site (e.g., TEV) which may be associated with or included in the delivery vehicle. In some embodiments, the at least one tracking system comprises the inclusion of at least one functional sequence or protein that comprises a protease cleavage site (e.g., TEV) which may be associated with, encoded in or included in the benchmark construct. [0790] In some embodiments, the at least one tracking system comprises the inclusion of at least one functional sequence or protein that comprises an affinity tag (e.g.3xHA, FLAG, His) which may be associated with or included in the delivery vehicle. In some embodiments, the at least one tracking system comprises the inclusion of at least one functional sequence or protein that comprises an affinity tag (e.g.3xHA, FLAG, His) which may be associated with, encoded in or included in the benchmark construct. V. PHARMACEUTICAL COMPOSITION AND ROUTE OF ADMINISTRATION Pharmaceutical Compositions and Formulations [0791] The originator constructs, benchmark constructs, and targeting systems can be formulated using one or more excipients to: (1) increase stability; (2) increase cell transfection or transduction; (3) permit the sustained or delayed expression of the payload; (4) alter the biodistribution (e.g., target the viral particle to specific tissues or cell types); (5) increase the translation of encoded protein; (6) alter the release profile of encoded protein; and/or (7) allow for regulatable expression of the cargo and/or payload. [0792] Formulations can include, without limitation, saline, liposomes, lipid nanoparticles, polymers, peptides, proteins, cells transfected with viral vectors (e.g., for transfer or transplantation into a subject) and combinations thereof. [0793] Formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. As used herein the term "pharmaceutical composition" refers to compositions comprising at least one active ingredient and optionally one or more pharmaceutically acceptable excipients. [0794] In general, such preparatory methods include the step of associating the active ingredient with an excipient and/or one or more other accessory ingredients. As used herein, the phrase "active ingredient" generally refers either to an originator construct or benchmark construct with a payload region or cargo or payload as described herein. [0795] Formulations of the originator constructs, benchmark constructs, and targeting systems and pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with an excipient and/or one or more other accessory ingredients, and then, if necessary and/or desirable, dividing, shaping and/or packaging the product into a desired single- or multi-dose unit. [0796] A pharmaceutical composition in accordance with the present disclosure may be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, a "unit dose" refers to a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. [0797] In some embodiments, a pharmaceutically acceptable excipient may be at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% pure. In some embodiments, an excipient is approved for use for humans and for veterinary use. In some embodiments, an excipient may be approved by United States Food and Drug Administration. In some embodiments, an excipient may be of pharmaceutical grade. In some embodiments, an excipient may meet the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and/or the International Pharmacopoeia. [0798] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition in accordance with the present disclosure may vary, depending upon the identity, size, and/or condition of the subject being treated and further depending upon the route by which the composition is to be administered. For example, the composition may comprise between 0.1% and 99% (w/w) of the active ingredient. By way of example, the composition may comprise between 0.1% and 100%, e.g., between 0.5 and 50%, between 1-30%, between 5-80%, or at least 80% (w/w) active ingredient. [0799] In one aspect, the present disclosure further provides delivery systems for delivery of a therapeutic payload disclosed herein. In some embodiments, a delivery system suitable for delivery of the therapeutic payload disclosed herein comprises a lipid nanoparticle (LNP) formulation. [0800] In some embodiments, an LNP of the present disclosure comprises an ionizable lipid, a structural lipid, a PEGylated lipid (aka PEG lipid), and a phospholipid. In alternative embodiments, an LNP comprises an ionizable lipid, a structural lipid, a PEGylated lipid (aka PEG lipid), and a zwitterionic amino acid lipid. In some embodiments, an LNP further comprises a 5 th lipid, besides any of the aforementioned lipid components. In some embodiments, the LNP encapsulates one or more elements of the active agent of the present disclosure. In some embodiments, an LNP further comprises a targeting moiety covalently or non-covalently bound to the outer surface of the LNP. In some embodiments, the targeting moiety is a targeting moiety that binds to, or otherwise facilitates uptake by, cells of a particular organ system. [0801] In some embodiments, an LNP has a diameter of at least about 20nm, 30 nm, 40nm, 50nm, 60nm, 70nm, 80nm, or 90nm. In some embodiments, an LNP has a diameter of less than about 100nm, 110nm, 120nm, 130nm, 140nm, 150nm, or 160nm. In some embodiments, an LNP has a diameter of less than about 100nm. In some embodiments, an LNP has a diameter of less than about 90nm. In some embodiments, an LNP has a diameter of less than about 80nm. In some embodiments, an LNP has a diameter of about 60-100nm. In some embodiments, an LNP has a diameter of about 75-80nm. [0802] In some embodiments, the lipid nanoparticle compositions of the present disclosure are described according to the respective molar ratios of the component lipids in the formulation. As a non-limiting example, the mol-% of the ionizable lipid may be from about 10 mol-% to about 80 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 20 mol-% to about 70 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 30 mol-% to about 60 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 35 mol-% to about 55 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 40 mol-% to about 50 mol-%. [0803] In some embodiments, the mol-% of the phospholipid may be from about 1 mol-% to about 50 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 2 mol-% to about 45 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 3 mol-% to about 40 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 4 mol-% to about 35 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 5 mol-% to about 30 mol-%. In some embodiments, the mol- % of the phospholipid may be from about 10 mol-% to about 20 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 5 mol-% to about 20 mol-%. [0804] In some embodiments, the mol-% of the structural lipid may be from about 10 mol-% to about 80 mol-%. In some embodiments, the mol-% of the structural lipid may be from about 20 mol-% to about 70 mol-%. In some embodiments, the mol-% of the structural lipid may be from about 30 mol-% to about 60 mol-%. In some embodiments, the mol-% of the structural lipid may be from about 35 mol-% to about 55 mol-%. In some embodiments, the mol-% of the structural lipid may be from about 40 mol-% to about 50 mol-%. [0805] In some embodiments, the mol-% of the PEG lipid may be from about 0.1 mol-% to about 10 mol-%. In some embodiments, the mol-% of the PEG lipid may be from about 0.2 mol-% to about 5 mol-%. In some embodiments, the mol-% of the PEG lipid may be from about 0.5 mol-% to about 3 mol-%. In some embodiments, the mol-% of the PEG lipid may be from about 1 mol-% to about 2 mol-%. In some embodiments, the mol-% of the PEG lipid may be about 1.5 mol-%. [0806] In some embodiments, a nanoparticle includes an ionizable lipid, a phospholipid, a PEG lipid, and a structural lipid. In certain embodiments, the lipid component of the nanoparticle composition includes about 30 mol % to about 60 mol % ionizable lipid, about 0 mol % to about 30 mol % phospholipid, about 18.5 mol % to about 48.5 mol % structural lipid, and about 0 mol% to about 10 mol% of PEG lipid, provided that the total mol % does not exceed 100%. In some embodiments, the lipid component of the nanoparticle composition includes about 35 mol % to about 55 mol % ionizable lipid, about 5 mol % to about 25 mol % phospholipid, about 30 mol % to about 40 mol % structural lipid, and about 0 mol % to about 10 mol % of PEG lipid. In a particular embodiment, the lipid component includes about 50 mol % ionizable lipid, about 10 mol % phospholipid, about 38.5 mol % structural lipid, and about 1.5 mol% of PEG lipid. In another particular embodiment, the lipid component includes about 40 mol % ionizable lipid, about 20 mol % phospholipid, about 38.5 mol % structural lipid, and about 1.5 mol % of PEG lipid. In another particular embodiment, the lipid component includes about 48.5 mol % ionizable lipid, about 10 mol % phospholipid, about 40 mol % structural lipid, and about 1.5 mol % of PEG lipid. In another particular embodiment, the lipid component includes about 48.5 mol % ionizable lipid, about 10 mol % phospholipid, about 39 mol % structural lipid, and about 2.5 mol % of PEG lipid. In some embodiments, the phospholipid may be DOPE or DSPC. In other embodiments, the PEG lipid may be PEG-DMG and/or the structural lipid may be cholesterol. The amount of active agent in a nanoparticle composition may depend on the size, composition, desired target and/or application, or other properties of the nanoparticle composition as well as on the properties of the active agent. For example, the amount of active agent useful in a nanoparticle composition may depend on the size, sequence, and other characteristics of the active agent. The relative amounts of active agent and other elements (e.g., lipids) in a nanoparticle composition may also vary. In some embodiments, the wt/wt ratio of the lipid component to an enzyme in a nanoparticle composition may be from about 5:1 to about 60:1, such as 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, and 60:1. The amount of a enzyme in a nanoparticle composition may, for example, be measured using absorption spectroscopy (e.g., ultraviolet-visible spectroscopy). [0807] In some embodiments, a nanoparticle composition comprising an active agent of the present disclosure is formulated to provide a specific E:P ratio. The E:P ratio of the composition refers to the molar ratio of nitrogen atoms in one or more lipids to the number of phosphate groups in an RNA active agent. In general, a lower E:P ratio is preferred. The one or more enzymes, lipids, and amounts thereof may be selected to provide an E:P ratio from about 2:1 to about 30:1, such as 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12:1, 14:1, 16:1, 18:1, 20:1, 22:1, 24:1, 26:1, 28:1, or 30:1. In certain embodiments, the E:P ratio may be from about 2:1 to about 8:1. In other embodiments, the E:P ratio is from about 5:1 to about 8:1. For example, the E:P ratio may be about 5.0:1, about 5.5:1, about 5.67:1, about 6.0:1, about 6.5:1, or about 7.0:1. [0808] The characteristics of a nanoparticle composition may depend on the components thereof. For example, a nanoparticle composition including cholesterol as a structural lipid may have different characteristics than a nanoparticle composition that includes a different structural lipid. Similarly, the characteristics of a nanoparticle composition may depend on the absolute or relative amounts of its components. For instance, a nanoparticle composition including a higher molar fraction of a phospholipid may have different characteristics than a nanoparticle composi tion including a lower molar fraction of a phospholipid. Characteristics may also vary depending on the method and conditions of preparation of the nanoparticle composition. Nanoparticle compositions may be characterized by a variety of methods. For example, microscopy (e.g., transmission electron microscopy or scanning electron microscopy) may be used to examine the morphology and size distribution of a nanoparticle composition. Dynamic light scattering or potentiometry (e.g., potentiometric titrations) may be used to measure Zeta potentials. Dynamic light scattering may also be utilized to determine particle sizes. Instruments such as the Zetasizer Nano ZS (Malvern Instruments Ltd, Malvern, Worcestershire, UK) may also be used to measure multiple characteristics of a nanoparticle composition, Such as particle size, polydispersity index, and Zeta potential. [0809] The mean size of a nanoparticle composition may be between 10s of nm and 100s of nm, e.g., measured by dynamic light scattering (DLS). For example, the mean size may be from about 40 nm to about 150 nm, such as about 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, or 150 nm. In some embodiments, the mean size of a nanoparticle composition may be from about 50 nm to about 100 nm, from about 50 nm to about 90 nm, from about 50 nm to about 80 nm, from about 50 nm to about 70 nm, from about 50 nm to about 60 nm, from about 60 nm to about 100 nm, from about 60 nm to about 90 nm, from about 60 nm to about 80 nm, from about 60 nm to about 70 nm, from about 70 nm to about 100 nm, from about 70 nm to about 90 nm, from about 70 nm to about 80 nm, from about 80 nm to about 100 nm, from about 80 nm to about 90 nm, or from about 90 nm to about 100 nm. In certain embodiments, the mean size of a nanoparticle composition may be from about 70 nm to about 100 nm. In a particular embodiment, the mean size may be about 80 nm. In other embodiments, the mean size may be about 100 nm. [0810] A nanoparticle composition may be relatively homogenous. A polydispersity index may be used to indicate the homogeneity of a nanoparticle composition, e.g., the particle size distribution of the nanoparticle compositions. A small (e.g., less than 0.3) polydispersity index generally indicates a narrow particle size distribution. A nanoparticle composition may have a polydispersity index from about 0 to about 0.25, such as 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, or 0.25. [0811] The Zeta potential of a nanoparticle composition may be used to indicate the electrokinetic potential of the composition. For example, the Zeta potential may describe the surface charge of a nanoparticle composition. Nanoparticle compositions with relatively low charges, positive or negative, are generally desirable, as more highly charged species may interact undesirably with cells, tissues, and other elements in the body. In some embodiments, the Zeta potential of a nanoparticle composition may be from about -10 mV to about +20 mV, from about -10 mV to about +15 mV, from about -10 mV to about +10 mV, from about -10 mV to about +5 mV, from about -10 mV to about 0 mV, from about -10 mV to about -5 mV, from about -5 mV to about +20 mV, from about -5 mV to about +15 mV, from about -5 mV to about +10 mV, from about -5 mV to about +5 mV, from about -5 mV to about 0 mV, from about 0 mV, to about +20 mV, from about 0 mV to about +15 mV, from about 0 mV to about +10 mV, from about 0 mV to about +5 mV, from about +5 mV to about +20 mV, from about +5 mV, to about +15 mV, or from about +5 mV to about +10 mV. [0812] The efficiency of encapsulation of a payload describes the amount of payload that is encapsulated or otherwise associated with a nanoparticle composition after preparation, relative to the initial amount provided. The encapsulation efficiency is desirably high (e.g., close to 100%). The encapsulation efficiency may be measured, for example, by comparing the amount of payload in a solution containing the nanoparticle composition before and after breaking up the nanoparticle composition with one or more organic solvents or detergents. Fluorescence may be used to measure the amount of free payload in a solution. For the nanoparticle compositions described herein, the encapsulation efficiency of a therapeutic and/or prophylactic may be at least 50%, for example 50%, 55%, 60%.65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. In some embodiments, the encapsulation efficiency may be at least 80%. In certain embodiments, the encapsulation efficiency may be at least 90%. [0813] Lipids and their method of preparation are disclosed in, e.g., U.S. Patent Nos. 8,569,256, 5,965,542 and U.S. Patent Publication Nos. 2016/0199485, 2016/0009637, 2015/0273068, 2015/0265708, 2015/0203446, 2015/0005363, 2014/0308304, 2014/0200257, 2013/086373, 2013/0338210, 2013/0323269, 2013/0245107, 2013/0195920, 2013/0123338, 2013/0022649, 2013/0017223, 2012/0295832, 2012/0183581, 2012/0172411, 2012/0027803, 2012/0058188, 2011/0311583, 2011/0311582, 2011/0262527, 2011/0216622, 2011/0117125, 2011/0091525, 2011/0076335, 2011/0060032, 2010/0130588, 2007/0042031, 2006/0240093, 2006/0083780, 2006/0008910, 2005/0175682, 2005/017054, 2005/0118253, 2005/0064595, 2004/0142025, 2007/0042031, 1999/009076 and PCT Pub. Nos. WO 99/39741, WO 2017/117528, WO 2017/004143, WO 2017/075531, WO 2015/199952, WO 2014/008334, WO 2013/086373, WO 2013/086322, WO 2013/016058, WO 2013/086373, WO2011/141705, and WO 2001/07548 and Semple et. al, Nature Biotechnology, 2010, 28, 172-176, the full disclosures of which are herein incorporated by reference in their entirety for all purposes. [0814] A nanoparticle composition may include any substance useful in pharmaceutical compositions. For example, the nanoparticle composition may include one or more pharmaceutically acceptable excipients or accessory ingredients such as, but not limited to, one or more solvents, dispersion media, diluents, dispersion aids, suspension aids, granulating aids, disintegrants, fillers, glidants, liquid vehicles, binders, surface active agents, isotonic agents, thickening or emulsifying agents, buffering agents, lubricating agents, oils, preservatives, and other species. Excipients such as waxes, butters, coloring agents, coating agents, flavorings, and perfuming agents may also be included. Pharmaceutically acceptable excipients are well known in the art (see for example Remington’s The Science and Practice of Pharmacy, 21 st Edition, A. R. Gennaro: Lippincott, Williams & Wilkins, Baltimore, Md., 2006). Excipients and Diluents [0815] Excipients, as used herein, include, but are not limited to, any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, and the like, as suited to the particular dosage form desired. Various excipients for formulating pharmaceutical compositions and techniques for preparing the composition are known in the art (see Remington: The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro, Lippincott, Williams & Wilkins, Baltimore, MD, 2006; incorporated herein by reference in its entirety). The use of a conventional excipient medium may be contemplated within the scope of the present disclosure, except insofar as any conventional excipient medium may be incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition. [0816] Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and/or combinations thereof. Ionizable lipids [0817] In some embodiments, an LNP disclosed herein comprises an ionizable lipid. In some embodiments, an LNP comprises two or more ionizable lipids. In some embodiments, the ionizable lipid is any ionizable lipid disclosed herein, or any combinations thereof. Structural lipids [0818] In some embodiments, an LNP comprises a structural lipid. Structural lipids can be selected from the group consisting of, but are not limited to, cholesterol, fecosterol, fucosterol, beta sitosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, cholic acid, sitostanol, litocholic acid, tomatine, ursolic acid, alpha-tocopherol, Vitamin D3, Vitamin D2, Calcipotriol, botulin, lupeol, oleanolic acid, beta-sitosterol-acetate and mixtures thereof. In some embodiments, the structural lipid is cholesterol. In some embodiments, the structural lipid is a cholesterol analogue disclosed by Patel, et al., Nat Commun., 11, 983 (2020), which is incorporated herein by reference in its entirety. In some embodiments, the structural lipid includes cholesterol and a corticosteroid (such as prednisolone, dexamethasone, prednisone, and hydrocortisone), or any combinations thereof. In some embodiments, a structural lipid is described in international patent application WO2019152557A1, which is incorporated herein by reference in its entirety. [0819] In some embodiments, a structural lipid is a cholesterol analog. Using a cholesterol analog may enhance endosomal escape as described in Patel et al., Naturally-occuring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA, Nature Communications (2020), which is incorporated herein by reference. [0820] In some embodiments, a structural lipid is a phytosterol. Using a phytosterol may enhance endosomal escape as described in Herrera et al., Illuminating endosomal escape of polymorphic lipid nanoparticles that boost mRNA delivery, Biomaterials Science (2020), which is incorporated herein by reference. [0821] In some embodiments, a structural lipid contains plant sterol mimetics for enhanced endosomal release. PEGylated lipids [0822] A PEGylated lipid is a lipid modified with polyethylene glycol. In some embodiments, the LNP comprises a compound of any of Formula IA, Formula IB, Formula IC, Formula ID, Formula I, or a compound of Table 1 or a pharmaceutically acceptable salt thereof, as described herein above. In some embodiments, the LNP comprises a compound of Formula I or a pharmaceutically acceptable salt thereof, as described herein above. In some embodiments, the LNP comprises a compound of Formula II or a pharmaceutically acceptable salt thereof, as described herein above. In some embodiments, the LNP comprises a compound of Formula IA or a pharmaceutically acceptable salt thereof, as described herein above. In some embodiments, the LNP comprises a compound of Formula IB or a pharmaceutically acceptable salt thereof, as described herein above. In some embodiments, the LNP comprises a compound of Formula IC or a pharmaceutically acceptable salt thereof, as described herein above. In some embodiments, the LNP comprises a compound of Formula ID or a pharmaceutically acceptable salt thereof, as described herein above. In some embodiments, the LNP comprises a compound set forth in Table (I), as described herein above. [0823] In some embodiments, an LNP comprises an additional PEGylated lipid or PEG- modified lipid. A PEGylated lipid may be selected from the non-limiting group consisting of PEG-modified phosphatidylethanolamines, PEG-modified phosphatidic acids, PEG-modified ceramides, PEG-modified dialkylamines, PEG-modified diacylglycerols, PEG-modified dialkylglycerols, and mixtures thereof. For example, a PEG lipid may be PEG-c-DOMG, PEG- DMG, PEG-DLPE, PEG-DMPE, PEG-DPPC, or a PEG-DSPE lipid. [0824] In some embodiments, the LNP comprises a PEGylated lipid disclosed in one of US 2019/0240354; US 2010/0130588; US 2021/0087135; WO 2021/204179; US 2021/0128488; US 2020/0121809; US 2017/0119904; US 2013/0108685; US 2013/0195920; US 2015/0005363; US 2014/0308304; US 2013/0053572; WO 2019/232095A1; WO 2021/077067; WO 2019/152557; US 2015/0203446; US 2017/0210697; US 2014/0200257; or WO 2019/089828A1, each of which is incorporated by reference herein in their entirety. [0825] In some embodiments, the LNP comprises a PEGylated lipid substitute in place of the PEGylated lipid. All embodiments disclosed herein that contemplate a PEGylated lipid should be understood to also apply to PEGylated lipid substitutes. In some embodiments, the LNP comprises a polysarcosine-lipid conjugate, such as those disclosed in US 2022/0001025 A1, which is incorporated by reference herein in its entirety. Phospholipids [0826] In some embodiments, an LNP of the present disclosure comprises a phospholipid. Phospholipids useful in the compositions and methods may be selected from the non-limiting group consisting of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn- glycero-3-phosphoethanolamine (DOPE), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1.2-dioleoyl-sn-glycero-3- phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2- diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3- phosphocho line (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2-cholesterylhemisuc cinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1- hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3- phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl- sn-glycero-3-phosphocholine, 1,2-diphytanoylsn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3- phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2- diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3- phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), sodium (S)-2-ammonio-3-((((R)-2-(oleoyloxy)-3- (stearoyloxy)propoxy)oxidophosphoryl)oxy)propanoate (L-α-phosphatidylserine; Brain PS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dioleoyl-phosphatidylethanolamine4-(N- maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dioleoylphosphatidylglycerol (DOPG), 1,2-dioleoyl-sn-glycero-3-(phospho-L-serine) (DOPS), acell-fusogenicphospholipid (DPhPE), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylcholine (DSPC), distearoyl-phosphatidyl-ethanolamine (DSPE), distearoyl phosphoethanolamineimidazole (DSPEI), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), egg phosphatidylcholine (EPC), 1,2-dioleoyl-sn-glycero-3-phosphate (18:1 PA; DOPA), ammonium bis((S)-2-hydroxy- 3-(oleoyloxy)propyl) phosphate (18:1 DMP; LBPA), 1,2-dioleoyl-sn-glycero-3-phospho-(1’- myo-inositol) (DOPI; 18:1 PI), 1,2-distearoyl-sn-glycero-3-phospho-L-serine (18:0 PS), 1,2- dilinoleoyl-sn-glycero-3-phospho-L-serine (18:2 PS), 1-palmitoyl-2-oleoyl-sn-glycero-3- phospho-L-serine (16:0-18:1 PS; POPS), 1-stearoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (18:0-18:1 PS), 1-stearoyl-2-linoleoyl-sn-glycero-3-phospho-L-serine (18:0-18:2 PS), 1- oleoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:1 Lyso PS), 1-stearoyl-2-hydroxy-sn- glycero-3-phospho-L-serine (18:0 Lyso PS), and sphingomyelin. In some embodiments, an LNP includes DSPC. In certain embodiments, an LNP includes DOPE. In some embodiments, an LNP includes both DSPC and DOPE. [0827] In some embodiments, a phospholipid tail may be modified in order to promote endosomal escape as described in U.S. 2021/0121411, which is incorporated herein by reference. [0828] In some embodiments, the LNP comprises a phospholipid disclosed in one of US 2019/0240354; US 2010/0130588; US 2021/0087135; WO 2021/204179; US 2021/0128488; US 2020/0121809; US 2017/0119904; US 2013/0108685; US 2013/0195920; US 2015/0005363; US 2014/0308304; US 2013/0053572; WO 2019/232095A1; WO 2021/077067; WO 2019/152557; US 2017/0210697; or WO 2019/089828A1, each of which is incorporated by reference herein in their entirety. [0829] In some embodiments, phospholipids disclosed in US 2020/0121809 have the following structure: [0830] wherein R 1 and R 2 are each independently a branched or straight, saturated or unsaturated carbon chain (e.g., alkyl, alkenyl, alkynyl). Targeting moieties [0831] In some embodiments, the lipid nanoparticle further comprises a targeting moiety. The targeting moiety may be an antibody or a fragment thereof. The targeting moiety may be capable of binding to a target antigen. [0832] In some embodiments, the pharmaceutical composition comprises a targeting moiety that is operably connected to a lipid nanoparticle. In some embodiments, the targeting moiety is capable of binding to a target antigen. In some embodiments, the target antigen is expressed in a target organ. In some embodiments, the target antigen is expressed more in the target organ than it is in the liver. [0833] In some embodiments, the targeting moiety is an antibody as described in WO2016189532A1, which is incorporated herein by reference. For example, in some embodiments, the targeted particles are conjugated to a specific anti-CD38 monoclonal antibody (mAb), which allows specific delivery of the siRNAs encapsulated within the particles at a greater percentage to B-cell lymphocytes malignancies (such as MCL) than to other subtypes of leukocytes. [0834] In some embodiments, the lipid nanoparticles may be targeted when conjugated/attached/associated with a targeting moiety such as an antibody. Zwitterionic amino lipids [0835] In some embodiments, an LNP comprises a zwitterionic lipid. In some embodiments, an LNP comprising a zwitterionic lipid does not comprise a phospholipid. [0836] Zwitterionic amino lipids have been shown to be able to self-assemble into LNPs without phospholipids to load, stabilize, and release mRNAs intracellular as described in U.S. Patent Application 20210121411, which is incorporated herein by reference in its entirety. Zwitterionic, ionizable cationic and permanently cationic helper lipids enable tissue-selective mRNA delivery and CRISPR-Cas9 gene editing in spleen, liver and lungs as described in Liu et al., Membrane-destablizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR-Cas gene editing, Nat Mater. (2021), which is incorporated herein by reference in its entirety. [0837] The zwitterionic lipids may have head groups containing a cationic amine and an anionic carboxylate as described in Walsh et al., Synthesis, Characterization and Evaluation of Ionizable Lysine-Based Lipids for siRNA Delivery, Bioconjug Chem. (2013), which is incorporated herein by reference in its entirety. Ionizable lysine-based lipids containing a lysine head group linked to a long-chain dialkylamine through an amide linkage at the lysine α-amine may reduce immunogenicity as described in Walsh et al., Synthesis, Characterization and Evaluation of Ionizable Lysine-Based Lipids for siRNA Delivery, Bioconjug Chem. (2013). Additional Lipid Components [0838] In some embodiments, the LNP compositions of the present disclosure further comprise one or more additional lipid components capable of influencing the tropism of the LNP. In some embodiments, the LNP further comprises at least one lipid selected from DDAB, EPC, 14PA, 18BMP, DODAP, DOTAP, and C12-200 (see Cheng, et al. Nat Nanotechnol. 2020 April; 15(4): 313–320.; Dillard, et al. PNAS 2021 Vol.118 No.52.). Polynucleotides [0839] In some embodiments, an LNP of the present disclosure contains an active agent. In some embodiments, an active agent is a polynucleotide. In some embodiments, a LNP is capable of delivering a polynucleotide to a target organ. A polynucleotide, in its broadest sense of the term, includes any compound and/or substance that is or can be incorporated into an oligonucleotide chain. Exemplary polynucleotides for use in accordance with the present disclosure include, but are not limited to, one or more of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) including messenger mRNA (mRNA), hybrids thereof, RNAi- inducing agents, RNAi agents, siRNAs, shRNAs, miRNAs, antisense RNAs, ribozymes, catalytic DNA, RNAs that induce triple helix formation, aptamers, vectors, etc. RNAs useful in the compositions and methods described herein can be selected from the group consisting of but are not limited to, shortimers, antagomirs, antisense, ribozymes, short interfering RNA (siRNA), asymmetrical interfering RNA (aiRNA), microRNA (miRNA), Dicer substrate RNA (dsRNA), short hairpin RNA (shRNA), transfer RNA (tRNA), messenger RNA (mRNA), and mixtures thereof. In some embodiments, a polynucleotide is mRNA. In some embodiments, a polynucleotide is circular RNA. In some embodiments, a polynucleotide encodes a protein. A polynucleotide may encode any polypeptide of interest, including any naturally or non- naturally occurring or otherwise modified polypeptide. A polypeptide may be of any size and may have any secondary structure or activity. In some embodiments, a polypeptide encoded by an mRNA may have a therapeutic effect when expressed in a cell. [0840] In other embodiments, a polynucleotide is an siRNA. An siRNA may be capable of selectively knocking down or down regulating expression of a gene of interest. For example, an siRNA could be selected to silence a gene associated with a particular disease, disorder, or condition upon administration to a subject in need thereof of a nanoparticle composition including the siRNA. An siRNA may comprise a sequence that is complementary to an mRNA sequence that encodes a gene or protein of interest. In some embodiments, the siRNA may be an immunomodulatory siRNA. [0841] In some embodiments, a polynucleotide is an shRNA or a vector or plasmid encoding the same. An shRNA may be produced inside a target cell upon delivery of an appropriate construct to the nucleus. Constructs and mechanisms relating to shRNA are well known in the relevant arts. [0842] A polynucleotide may include a first region of linked nucleosides encoding a polypeptide of interest (e.g., a coding region), a first flanking region located at the 5'-terminus of the first region (e.g., a 5'-UTR), a second flanking region located at the 3'-terminus of the first region (e.g., a 3'-UTR), at least one 5'-cap region, and a 3'-stabilizing region. In some embodiments, a polynucleotide further includes a poly-A region or a Kozak sequence (e.g., in the 5'-UTR). In some cases, polynucleotides may contain one or more intronic nucleotide sequences capable of being excised from the polynucleotide. In some embodiments, a polynucleotide (e.g., an mRNA) may include a 5'cap structure, a chain terminating nucleotide, a stem loop, a polyA sequence, and/or a polyadenylation signal. Any one of the regions of a nucleic acid may include one or more alternative components (e.g., an alternative nucleoside). For example, the 3'-stabilizing region may contain an alternative nucleoside such as an L- nucleoside, an inverted thymidine, or a 2'-O-methyl nucleoside and/or the coding region, 5'- UTR, 3'-UTR, or cap region may include an alternative nucleoside such as a 5-substituted uridine (e.g., 5-methoxyu ridine), a 1-substituted pseudouridine (e.g., 1-methyl pseudouridine or 1-ethyl-pseudouridine), and/or a 5-substituted cytidine (e.g., 5-methyl-cytidine). In some embodiments, a polynucleotide contains only naturally occurring nucleosides. [0843] In some cases, a polynucleotide is greater than 30 nucleotides in length. In another embodiment, the poly nucleotide molecule is greater than 35 nucleotides in length. In another embodiment, the length is at least 40 nucleotides. In another embodiment, the length is at least 45 nucleotides. In another embodiment, the length is at least 55 nucleotides. In another embodiment, the length is at least 50 nucleotides. In another embodiment, the length is at least 60 nucleotides. In another embodiment, the length is at least 80 nucleotides. In another embodiment, the length is at least 90 nucleotides. In another embodiment, the length is at least 100 nucleotides. In another embodiment, the length is at least 120 nucleotides. In another embodiment, the length is at least 140 nucleotides. In another embodiment, the length is at least 160 nucleotides. In another embodiment, the length is at least 180 nucleotides. In another embodiment, the length is at least 200 nucleotides. In another embodiment, the length is at least 250 nucleotides. In another embodiment, the length is at least 300 nucleotides. In another embodiment, the length is at least 350 nucleotides. In another embodiment, the length is at least 400 nucleotides. In another embodiment, the length is at least 450 nucleotides. In another embodiment, the length is at least 500 nucleotides. In another embodiment, the length is at least 600 nucleotides. In another embodiment, the length is at least 700 nucleotides. In another embodiment, the length is at least 800 nucleotides. In another embodiment, the length is at least 900 nucleotides. In another embodiment, the length is at least 1000 nucleotides. In another embodiment, the length is at least 1100 nucleotides. In another embodiment, the length is at least 1200 nucleotides. In another embodiment, the length is at least 1300 nucleotides. In another embodiment, the length is at least 1400 nucleotides. In another embodiment, the length is at least 1500 nucleotides. In another embodiment, the length is at least 1600 nucleotides. In another embodiment, the length is at least 1800 nucleotides. In another embodiment, the length is at least 2000 nucleotides. In another embodiment, the length is at least 2500 nucleotides. In another embodiment, the length is at least 3000 nucleotides. In another embodiment, the length is at least 4000 nucleotides. In another embodiment, the length is at least 5000 nucleotides, or greater than 5000 nucleotides. [0844] In some embodiments, a polynucleotide molecule, formula, composition or method associated therewith comprises one or more polynucleotides comprising features as described in WO2002/098443, WO2003/051401, WO2008/052770, WO2009/127230, WO2006/122828, WO2008/083949, WO2010/088927, WO2010/037539, WO2004/004743, WO2005/016376, WO2006/024518, WO2007/095,976, WO2008/014979, WO2008/077592, WO2009/030481, WO2009/095226, WO2011/069586, WO2011/026641, WO2011/144358, WO2012/019780, WO2012/013326, WO2012/089338, WO2012/113513, WO2012/116811, WO2012/116810, WO2013/113502, WO2013/113501, WO2013/113736, WO2013/143698, WO2013/143699, WO2013/143700, WO2013/120626, WO2013/120627, WO2013/120628, WO2013/120629, WO2013/174409, WO2014/127917, WO2015/024669, WO2015/024668, WO2015/024667, WO2015/024665, WO2015/024666, WO2015/024664, WO2015/101415, WO2015/101414, WO2015/024667, WO2015/062738, WO2015/101416, all of which are incorporated by reference herein. [0845] Polynucleotides, such as circular RNA, may contain an internal ribosome entry site (IRES). An IRES may act as the sole ribosome binding site, or may serve as one of multiple ribosome binding sites of an mRNA. A polynucleotide containing more than one functional ribosome binding site may encode several peptides or polypeptides that are translated independently by the ribosomes (e.g., multicistronic mRNA). When polynucleotides are provided with an IRES, further optionally provided is a second translatable region. Examples of IRES sequences that can be used according to the present disclosure include without limitation, those from picornaviruses (e.g., FMDV), pest viruses (CFFV), polio viruses (PV), encephalomyocarditis viruses (ECMV), foot-and mouth disease viruses (FMDV), hepatitis C viruses (HCV), classical Swine fever viruses (CSFV), murine leukemia virus (MLV), simian immune deficiency viruses (SIV) or cricket paralysis viruses (CrPV). [0846] In some embodiments, a polynucleotide comprises one or more microRNA binding sites. In some embodiments, a microRNA binding site is recognized by a microRNA in a non- target organ. In some embodiments, a microRNA binding site is recognized by a microRNA in the liver. In some embodiments, a microRNA binding site is recognized by a microRNA in hepatic cells. Inactive Ingredients [0847] In some embodiments, formulations described herein may comprise at least one inactive ingredient. As used herein, the term "inactive ingredient" refers to one or more agents that do not contribute to the activity of the active ingredient of the pharmaceutical composition included in formulations. In some embodiments, all, none or some of the inactive ingredients which may be used in the formulations of the present disclosure may be approved by the US Food and Drug Administration (FDA). [0848] In some embodiments, formulations disclosed herein may include cations or anions. The formulations include metal cations such as, but not limited to, Zn 2+ , Ca 2+ , Cu 2+ , Mn 2+ , Mg 2+ , and combinations thereof. As a non-limiting example, formulations may include polymers and complexes with a metal cation. [0849] Formulations of the disclosure may also include one or more pharmaceutically acceptable salts. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form (e.g., by reacting the free base group with a suitable organic acid). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Representative acid addition salts include acetate, acetic acid, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzene sulfonic acid, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. [0850] Solvates may be prepared by crystallization, recrystallization, or precipitation from a solution that includes organic solvents, water, or a mixture thereof. Examples of suitable solvents are ethanol, water (for example, mono-, di-, and tri-hydrates), N-methylpyrrolidinone (NMP), dimethyl sulfoxide (DMSO), N,N'-dimethylformamide (DMF), N,N'- dimethylacetamide (DMAC), 1,3-dimethyl-2-imidazolidinone (DMEU), 1,3-dimethyl-3,4,5,6- tetrahydro-2-(1H)-pyrimidinone (DMPU), acetonitrile (ACN), propylene glycol, ethyl acetate, benzyl alcohol, 2-pyrrolidone, benzyl benzoate, and the like. When water is the solvent, the solvate is referred to as a "hydrate." Routes of Administration [0851] The originator constructs, benchmark constructs, and targeting systems described herein may be administered by any delivery route which results in a therapeutically effective outcome. These include, but are not limited to, enteral (into the intestine), gastroenteral, epidural (into the dura mater), oral (by way of the mouth), transdermal, intracerebral (into the cerebrum), intracerebroventricular (into the cerebral ventricles), epicutaneous (application onto the skin), intradermal (into the skin itself), subcutaneous (under the skin), nasal administration (through the nose), intravenous (into a vein), intravenous bolus, intravenous drip, intra-arterial (into an artery), intramuscular (into a muscle), intracardiac (into the heart), intraosseous infusion (into the bone marrow), intrathecal (into the spinal canal), intraparenchymal (into brain tissue), intraperitoneal (infusion or injection into the peritoneum), intravesical infusion, intravitreal (through the eye), intracavernous injection (into a pathologic cavity) intracavitary (into the base of the penis), intravaginal administration, intrauterine, extra-amniotic administration, transdermal (diffusion through the intact skin for systemic distribution), transmucosal (diffusion through a mucous membrane), transvaginal, insufflation (snorting), sublingual, sublabial, enema, eye drops (onto the conjunctiva), ear drops, auricular (in or by way of the ear), buccal (directed toward the cheek), conjunctival, cutaneous, dental (to a tooth or teeth), electro-osmosis, endocervical, endosinusial, endotracheal, extracorporeal, hemodialysis, infiltration, interstitial, intra-abdominal, intra-amniotic, intra-articular, intrabiliary, intrabronchial, intrabursal, intracartilaginous (within a cartilage), intracaudal (within the cauda equine), intracisternal (within the cisterna magna cerebellomedularis), intracorneal (within the cornea), dental intracoronal, intracoronary (within the coronary arteries), intracorporus cavernosum (within the dilatable spaces of the corporus cavernosa of the penis), intradiscal (within a disc), intraductal (within a duct of a gland), intraduodenal (within the duodenum), intradural (within or beneath the dura), intraepidermal (to the epidermis), intraesophageal (to the esophagus), intragastric (within the stomach), intragingival (within the gingivae), intraileal (within the distal portion of the small intestine), intralesional (within or introduced directly to a localized lesion), intraluminal (within a lumen of a tube), intralymphatic (within the lymph), intramedullary (within the marrow cavity of a bone), intrameningeal (within the meninges), intramyocardial (within the myocardium), intraocular (within the eye), intraovarian (within the ovary), intrapericardial (within the pericardium), intrapleural (within the pleura), intraprostatic (within the prostate gland), intrapulmonary (within the lungs or its bronchi), intrasinal (within the nasal or periorbital sinuses), intraspinal (within the vertebral column), intrasynovial (within the synovial cavity of a joint), intratendinous (within a tendon), intratesticular (within the testicle), intrathecal (within the cerebrospinal fluid at any level of the cerebrospinal axis), intrathoracic (within the thorax), intratubular (within the tubules of an organ), intratumor (within a tumor), intratympanic (within the aurus media), intravascular (within a vessel or vessels), intraventricular (within a ventricle), iontophoresis (by means of electric current where ions of soluble salts migrate into the tissues of the body), irrigation (to bathe or flush open wounds or body cavities), laryngeal (directly upon the larynx), nasogastric (through the nose and into the stomach), occlusive dressing technique (topical route administration which is then covered by a dressing which occludes the area), ophthalmic (to the external eye), oropharyngeal (directly to the mouth and pharynx), parenteral, percutaneous, periarticular, peridural, perineural, periodontal, rectal, respiratory (within the respiratory tract by inhaling orally or nasally for local or systemic effect), retrobulbar (behind the pons or behind the eyeball), soft tissue, subarachnoid, subconjunctival, submucosal, topical, transplacental (through or across the placenta), transtracheal (through the wall of the trachea), transtympanic (across or through the tympanic cavity), ureteral (to the ureter), urethral (to the urethra), vaginal, caudal block, diagnostic, nerve block, biliary perfusion, cardiac perfusion, photopheresis, and spinal. [0852] In some embodiments, compositions may be administered in a way which allows them to cross the blood-brain barrier, vascular barrier, or other epithelial barrier. The originator constructs, benchmark constructs, and targeting systems may be administered in any suitable form, either as a liquid solution or suspension, as a solid form suitable for liquid solution or suspension in a liquid solution. The originator constructs, benchmark constructs, and targeting systems may be formulated with any appropriate and pharmaceutically acceptable excipient. [0853] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be delivered to a subject via a single route administration. [0854] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be delivered to a subject via a multi-site route of administration. A subject may be administered at 2, 3, 4, 5, or more than 5 sites. [0855] In some embodiments, a subject may be administered the originator constructs, benchmark constructs, and targeting systems using a bolus infusion. [0856] In some embodiments, a subject may be administered originator constructs, benchmark constructs, and targeting systems using sustained delivery over a period of minutes, hours, or days. The infusion rate may be changed depending on the subject, distribution, formulation or another delivery parameter. [0857] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be delivered by intramuscular delivery route. Non-limiting examples of intramuscular administration include an intravenous injection or a subcutaneous injection. [0858] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be delivered by oral administration. Non-limiting examples of oral delivery include a digestive tract administration and a buccal administration. [0859] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be delivered by intraocular delivery route. A non-limiting example of intraocular delivery include an intravitreal injection. [0860] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be delivered by intranasal delivery route. Non-limiting examples of intranasal delivery include nasal drops or nasal sprays. [0861] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be administered to a subject by peripheral injections. Non-limiting examples of peripheral injections include intraperitoneal, intramuscular, intravenous, conjunctival, or joint injection. [0862] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be delivered by injection into the cerebrospinal fluid. Non-limiting examples of delivery to the cerebrospinal fluid include intrathecal and intracerebroventricular administration. [0863] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be delivered by systemic delivery. As a non-limiting example, the systemic delivery may be by intravascular administration. [0864] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be administered to a subject by intracranial delivery. [0865] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be administered to a subject by intraparenchymal administration. [0866] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be administered to a subject by intramuscular administration. [0867] In some embodiments, the originator constructs, benchmark constructs, and targeting systems are administered to a subject and transduce muscle of a subject. As a non-limiting example, the originator constructs, benchmark constructs, and targeting systems are administered by intramuscular administration. [0868] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be administered to a subject by intravenous administration. [0869] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be administered to a subject by subcutaneous administration. [0870] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be administered to a subject by topical administration. [0871] In some embodiments, the originator constructs, benchmark constructs, and targeting systems may be delivered by more than one route of administration. [0872] The originator constructs, benchmark constructs, and targeting systems described herein may be co-administered in conjunction with one or more originator constructs, benchmark constructs, targeting systems, or therapeutic agents or moieties. VI. TARGET AREA, TISSUE OR CELL FOR DELIVERY [0873] The delivery of nucleic acid sequences, polypeptides or peptides and formulations thereof can be localized to specific target areas, tissues or cells using the methods and targeted delivery systems described herein. Tumors [0874] In some embodiments, the delivery of nucleic acid sequences, polypeptides or peptides and formulations thereof can be localized to a tumor. The tumor may be a benign tumor or a malignant tumor. [0875] In some embodiments, the delivery of nucleic acid sequences, polypeptides or peptides and formulations thereof is localized to a connective tissue tumor such as, but not limited to, adult fibrous tissue, embryonic (myxomatous) fibrous tissue, fat tissue, cartilage, bone, and notochord. As a non-limiting example, the tumor is a benign tumor called fibroma located in adult fibrous tissue. As a non-limiting example, the tumor is a malignant tumor called fibrosarcoma located in adult fibrous tissue. As a non-limiting example, the tumor is a benign tumor called myxoma located in embryonic fibrous tissue. As a non-limiting example, the tumor is a malignant tumor called myxosarcoma located in embryonic fibrous tissue. As a non- limiting example, the tumor is a benign tumor called lipoma located in fat tissue. As a non- limiting example, the tumor is a malignant tumor called liposarcoma located in fat tissue. As a non-limiting example, the tumor is a benign tumor called chondroma located in cartilage. As a non-limiting example, the tumor is a malignant tumor called chondrosarcoma located in cartilage. As a non-limiting example, the tumor is a benign tumor called osteoma located in bone. As a non-limiting example, the tumor is a malignant tumor called osteosarcoma located in bone. As a non-limiting example, the tumor is a malignant tumor called chordoma located in notochord. As a non-limiting example, the tumor is a benign tumor called fibrous histiocytoma located in connective tissue. As a non-limiting example, the tumor is a malignant tumor called malignant fibrous histiocytoma located in connective tissue. [0876] In some embodiments, the delivery of nucleic acid sequences, polypeptides or peptides and formulations thereof is localized to endothelium and/or mesothelium tumor tissue such as, but not limited to, blood vessels, lymph vessels and mesothelium. As a non-limiting example, the tumor is a benign tumor called hemangioma located in blood vessels. As a non-limiting example, the tumor is a benign tumor called hemangiopericytoma located in blood vessels. As a non-limiting example, the tumor is a malignant tumor called hemangiosarcoma located in blood vessels. As a non-limiting example, the tumor is a malignant tumor called angiosarcoma located in blood vessels. As a non-limiting example, the tumor is a benign tumor called lymphangioma located in lymph vessels. As a non-limiting example, the tumor is a malignant tumor called lymphangiosarcoma located in lymph vessels. As a non-limiting example, the tumor is a malignant tumor called mesothelioma located in the mesothelium. [0877] In some embodiments, the delivery of nucleic acid sequences, polypeptides or peptides and formulations thereof is localized to blood and lymphoid cell tissue such as, but not limited to, hematopoietic cells and lymphoid tissue. As a non-limiting example, the tumor is a benign tumor called preleukemias located in hematopoietic cells. As a non-limiting example, the tumor is a benign tumor called myeloproliferative disorders located in hematopoietic cells. As a non- limiting example, the tumor is a malignant tumor called leukemia located in hematopoietic cells. As a non-limiting example, the tumor is a benign tumor called plasmacytosis located in lymphoid tissue. As a non-limiting example, the tumor a malignant tumor called plasmacytoma located in lymphoid tissue. As a non-limiting example, the tumor a malignant tumor called multiple myeloma located in lymphoid tissue. As a non-limiting example, the tumor a malignant tumor called Hodgkin lymphoma located in lymphoid tissue. As a non-limiting example, the tumor a malignant tumor called Non-Hodgkin lymphoma located in lymphoid tissue. [0878] In some embodiments, the delivery of nucleic acid sequences, polypeptides or peptides and formulations thereof is localized to muscle tissue such as, but not limited to, smooth muscle and striated muscle. As a non-limiting example, the tumor is a benign tumor called Leiomyoma located in smooth muscle. As a non-limiting example, the tumor is a malignant tumor called leiomyosarcoma located in smooth muscle. As a non-limiting example, the tumor is a benign tumor called rhabdomyoma located in striated muscle. As a non-limiting example, the tumor is a malignant tumor called rhabdomyosarcoma located in striated muscle. [0879] In some embodiments, the delivery of nucleic acid sequences, polypeptides or peptides and formulations thereof is located to epithelial tissue such as, but not limited to, stratified squamous tissue, glandular epithelium tissue (e.g., liver, kidney, bile duct), transitional epithelium tissue, placenta and testis. As a non-limiting example, the tumor is a benign tumor called papilloma located in stratified squamous. As a non-limiting example, the tumor is a benign tumor called seborrheic keratosis located in stratified squamous. As a non-limiting example, the tumor is a malignant tumor called squamous cell carcinoma located in stratified squamous tissue. As a non-limiting example, the tumor is a malignant tumor called epidermoid carcinoma located in stratified squamous tissue. As a non-limiting example, the tumor is a benign tumor called adenoma located in glandular epithelium tissue. As a non-limiting example, the tumor is a benign tumor called hepatic adenoma located in liver glandular epithelium tissue. As a non-limiting example, the tumor is a benign tumor called renal tubular adenoma located in kidney glandular epithelium tissue. As a non-limiting example, the tumor is a benign tumor called bile duct adenoma located in bile duct glandular epithelium tissue. As a non-limiting example, the tumor is a malignant tumor called adenocarcinoma located in glandular epithelium tissue. As a non-limiting example, the tumor is a malignant tumor called hepatoma located in liver glandular epithelium tissue. As a non-limiting example, the tumor is a malignant tumor called hepatocellular carcinoma located in liver glandular epithelium tissue. As a non-limiting example, the tumor is a malignant tumor called renal cell carcinoma located in kidney glandular epithelium tissue. As a non-limiting example, the tumor is a malignant tumor called hypernephroma located in kidney glandular epithelium tissue. As a non-limiting example, the tumor is a malignant tumor called cholangiocarcinoma located in bile duct glandular epithelium tissue. As a non-limiting example, the tumor is a benign tumor called transitional cell papilloma located in transitional epithelium tissue. As a non-limiting example, the tumor is a malignant tumor called transitional cell carcinoma located in transitional epithelium tissue. As a non-limiting example, the tumor is a benign tumor called hydatidiform mole located in the placenta. As a non-limiting example, the tumor is a malignant tumor called choriocarcinoma located in the placenta. As a non-limiting example, the tumor is a malignant tumor called seminoma located in the testis. As a non-limiting example, the tumor is a malignant tumor called embryonal cell carcinoma located in the testis. [0880] In some embodiments, the delivery of nucleic acid sequences, polypeptides or peptides and formulations thereof is located to neural tissue such as, but not limited to, glial cells, nerve cells, meninges, and nerve sheath. As a non-limiting example, the tumor is a malignant tumor called glioma (grades I-III) located in glial cells. As a non-limiting example, the tumor is a malignant tumor called anaplastic glioma (grades I-III) located in glial cells. As a non-limiting example, the tumor is a malignant tumor called glioblastoma multiforme (grade IV) located in glial cells. As a non-limiting example, the tumor is a benign tumor called ganglioneuroma located in nerve cells. As a non-limiting example, the tumor is a malignant tumor called neuroblastoma located in nerve cells. As a non-limiting example, the tumor is a malignant tumor called medulloblastoma located in nerve cells. As a non-limiting example, the tumor is a benign tumor called meningioma located in meninges tissue. As a non-limiting example, the tumor is a malignant tumor called malignant meningioma located in meninges tissue. As a non- limiting example, the tumor is a benign tumor called schwannoma located in the nerve sheath. As a non-limiting example, the tumor is a benign tumor called neurilemmoma located in the nerve sheath. As a non-limiting example, the tumor is a benign tumor called neurofibroma located in the nerve sheath. As a non-limiting example, the tumor is a malignant tumor called malignant meningioma located in the nerve sheath. As a non-limiting example, the tumor is a malignant tumor called malignant schwannoma located in the nerve sheath. As a non-limiting example, the tumor is a malignant tumor called neurofibrosarcoma located in the nerve sheath. [0881] In some embodiments, the delivery of nucleic acid sequences, polypeptides or peptides and formulations thereof is located to the Amine Precursor Uptake and Decarboxylation (APUD) System such as, but not limited to, pituitary tissue, parathyroid tissue, thyroid tissue, bronchial tissue, adrenalmedulla tissue, pancreas tissue, stomach and intestines, carotid body and chemo-receptor system tissue. The APUD system is a series of cells which have endocrine functions and secrete a variety of small amine or polypeptide hormones. As a non-limiting example, the tumor is a benign tumor called basophilic adenoma located in the pituitary tissue. As a non-limiting example, the tumor is a benign tumor called eosinophilic adenoma located in the pituitary tissue. As a non-limiting example, the tumor is a benign tumor called chromophobe adenoma located in the pituitary tissue. As a non-limiting example, the tumor is a benign tumor called parathyroid adenoma located in the parathyroid. As a non-limiting example, the tumor is a malignant tumor called parathyroid carcinoma located in the parathyroid. As a non-limiting example, the tumor is a benign tumor called c cell hyperplasia located in the thyroid tissue (C cells). As a non-limiting example, the tumor is a malignant tumor called medullary carcinoma of thyroid located in the thyroid tissue (C cells). As a non- limiting example, the tumor is a malignant tumor called bronchial carcinooid located in the bronchial lining (Kultschitzky cells). As a non-limiting example, the tumor is a malignant tumor called oat cells carcinoma located in the bronchial lining (Kultschitzky cells). As a non- limiting example, the tumor is a benign tumor called pheochromocytoma located in the adrenalmedulla. As a non-limiting example, the tumor is a malignant tumor called malignant pheochromocytoma located in the adrenalmedualla. As a non-limiting example, the tumor is a benign tumor called islet cell adenoma located in the pancreas. As a non-limiting example, the tumor is a benign tumor called insulinoma located in the pancreas. As a non-limiting example, the tumor is a benign tumor called gastrinoma located in the pancreas. As a non-limiting example, the tumor is a malignant tumor called islet cell carcinoma located in the pancreas. As a non-limiting example, the tumor is a benign tumor called carcinoid located in the stomach and intestines. As a non-limiting example, the tumor is a malignant tumor called malignant carcinoid located in the stomach and intestines. As a non-limiting example, the tumor is a benign tumor called chemodectoma located in the carotid body and chemo-receptor system. As a non-limiting example, the tumor is a benign tumor called paraganglioma located in the carotid body and chemo-receptor system. As a non-limiting example, the tumor a malignant tumor called malignant carcinoid located in the carotid body and chemo-receptor system. As a non- limiting example, the tumor a malignant tumor called malignant paraganglioma located in the carotid body and chemo-receptor system. [0882] In some embodiments, the delivery of nucleic acid sequences, polypeptides or peptides and formulations thereof is located in neural crest-derived cells such as, but not limited to, pigment-producing cells (e.g., skin and eyes), schwann cells of the peripheral nervous system, and merkel cells in the squamous epithelium. As a non-limiting example, the tumor is a benign tumor called nevus located in pigment-producing cells such as the skin and eyes. As a non- limiting example, the tumor a malignant tumor called melanoma located in pigment-producing cells such as the skin and eyes. As a non-limiting example, the tumor is a benign tumor called schwannoma or neurilemmoma located in schwann cells of the peripheral nervous system. As a non-limiting example, the tumor is a malignant tumor called malignant schwannoma located in schwann cells of the peripheral nervous system. As a non-limiting example, the tumor is a malignant tumor called merkel cell neoplasm located in merkel cells in the squamous epithelium. [0883] In some embodiments, the delivery of nucleic acid sequences, polypeptides or peptides and formulations thereof is located in breast tissue. As a non-limiting example, the tumor is a benign tumor called fibroadenoma. As a non-limiting example, the tumor is a malignant tumor called cystosarcoma phylloides. [0884] In some embodiments, the delivery of nucleic acid sequences, polypeptides or peptides and formulations thereof is located in renal anlage tissue. As a non-limiting example, the tumor is a malignant tumor called Wilms tumor. [0885] In some embodiments, the delivery of nucleic acid sequences, polypeptides or peptides and formulations thereof is located in ovary tissue. [0886] In some embodiments, the delivery of nucleic acid sequences, polypeptides or peptides and formulations thereof is located in testis tissue. [0887] In some embodiments, the delivery of nucleic acid sequences, polypeptides or peptides and formulations thereof is located in germ cell tumor tissue. Non-limiting examples of germ cell tumors including seminoma, dysgerminoma, choriocarcinoma, embryonal carcinoma, endodermal sinus tumor, and teratocarcinoma. [0888] In some embodiments, the delivery of nucleic acid sequences, polypeptides or peptides and formulations thereof is located in the connective tissue stroma. Non-limiting examples of these tumors are Sertoli-Leydig cell tumors, arrhenoblastoma, granulose-theca cell tumors, hilar cell tumors, lipid cell tumors. Organs [0889] In some embodiments, the delivery of nucleic acid sequences, polypeptides or peptides and formulations thereof can be localized to an organ. Non-limiting example of organs include the anal canal, arteries, ascending colon, bladder, bone marrow, brain, bronchi, bronchioles, bulbourethral glands, capillaries, cecum, cerebellum, cerebral hemispheres, cerebrum, cervix, choroid plexus, clitoris, cranial nerves, descending colon, diencephalon, duodenum, ear, enteric nervous system, epididymis, esophagus, external reproductive organs, fallopian tubes, gallbladder, ganglia, gustatory, gut-associated lymphoid tissue, heart, ileum, internal reproductive organs, interstitium, jejunum, joints, kidneys, large intestine, larynx, ligaments, liver, lungs, lymph node, lymphatic vessel, mammary glands, medulla oblongata, mesentery, midbrain, mouth, muscles of breathing, nasal cavity, nerves, olfactory, ovaries, pancreas, parotid glands, penis, pharynx, placenta, pons, prostate, rectum, salivary glands, scrotum, seminal vesicles, sigmoid colon, skeleton, skin, small intestine, spinal nerves, spleen, stomach, subcutaneous tissue, sublingual glands, submandibular glands, teeth, tendons, testes, the brainstem, the spinal cord, the ventricular system, thymus, tongue, tonsils, trachea, transverse colon, ureter, urethra, uterus, vagina, vas deferens, veins, and vulva. Tissues [0890] In some embodiments, the delivery of nucleic acid sequences, polypeptides or peptides and formulations thereof can be localized to a tissue. Non-limiting example of adrenal medulla, adult fibrous tissue, blood vessels, bone, breast, bronchial lining, carotid body, cartilage, connective tissue, embryonic (myxomatous) fibrous tissue, epithelial, epithelium, fat, glandular epithelium (liver, kidney, bile duct), gonads, hematopoietic cells, lymph vessels, lymphoid tissue, meninges, mesothelium, muscle, nerve sheath, nervous, notochord, ovary, pancreas, parathyroid, pituitary, placenta, renal anlage, smooth muscle, stomach and intestines, stratified squamous, striated muscle, stroma, testis, thyroid, and transitional epithelium. As a non- limiting example, the tissue is connective tissue. Cells [0891] In some embodiments, the delivery of nucleic acid sequences, polypeptides or peptides and formulations thereof can be localized to a particular cell type. Non-limiting example of cells include adipocytes, adrenergic neural cells, alpha cell, amacrine cells, ameloblast, anterior lens epithelial cell, anterior/intermediate pituitary cells, apocrine sweat gland cell, astrocytes, auditory inner hair cells of organ of corti, auditory outer hair cells of organ of corti, b cell, bartholin's gland cell, basal cell (stem cell) of cornea, tongue, mouth, nasal cavity, distal anal canal, distal urethra, and distal vagina, basal cells of olfactory epithelium, basket cells, basophil granulocyte and precursors, beta cell, betz cells, bone marrow reticular tissue fibroblasts, border cells of organ of corti, boundary cells, bowman's gland cell, brown fat cell, brunner's gland cell, bulbourethral gland cell, bushy cells, c cells, cajal–retzius cells, cardiac muscle cell, cardiac muscle cells, cartwheel cells, cells of the zona fasciculata produce glucocorticoids, cells of the zona glomerulosa produce mineralocorticoids, cells of the zona reticularis produce androgens, cells of the adrenal cortex, cementoblast, centroacinar cell, ceruminous gland cell in ear, chandelier cells, chemoreceptor glomus cells of carotid body cell, chief cell, cholinergic neurons, chromaffin cells, club cell, cold-sensitive primary sensory neurons, connective tissue macrophage (all types), corneal fibroblasts (corneal keratocytes), corpus luteum cell of ruptured ovarian follicle secreting progesterone, cortical hair shaft cell, corticotropes, crystallin-containing lens fiber cell, cuticular hair shaft cell, cytotoxic t cell, d cell, delta cell, dendritic cell, double-bouquet cells, duct cell, eccrine sweat gland clear cell, eccrine sweat gland dark cell, efferent ducts cell, elastic cartilage chondrocyte, endothelial cells, enteric glial cells, enterochromaffin cell, enterochromaffin-like cell, enteroendocrine cell, eosinophil granulocyte and precursors, ependymal cells, epidermal basal cell, epidermal langerhans cell, epididymal basal cell, epididymal principal cell, epithelial reticular cell, epsilon cell, erythrocyte, fibrocartilage chondrocyte, fork neurons, foveolar cell, g cell, gall bladder epithelial cell, germ cells, gland of littre cell, gland of moll cell in eyelid, glial cells, golgi cells, gonadal stromal cells, gonadotropes, granule cells, granulosa cell, granulosa lutein cells, grid cells, head direction cells, and hematopoietic stem cells. In some embodiments, the at least one cell type comprise cancerous cells. In some embodiments, the at least one cell type comprise non-cancerous cells. In some embodiments, the at least one cell type comprise both cancerous and non-cancerous type. In some embodiments, the cancerous state of the at least one cell type is unknown. Physiological Systems [0892] In some embodiments, the delivery of nucleic acid sequences, polypeptides or peptides and formulations thereof can be localized to a physiological system. Non-limiting example of physiological system include the auditory, cardiovascular, central nervous system, chemo- receptor system, circulatory, digestive, endocrine, excretory, exocrine, genital, integumentary, lymphatic, muscular, musculoskeletal , nervous, peripheral nervous system, renal, reproductive, respiratory, urinary, and visual systems. VII. METHODS OF DETECTION AND ANALYSIS [0893] Detection of the tropism discovery platform including the targeting systems (e.g., candidate targeting system and validated targeting system) may be carried out through a variety of techniques (i.e., detection techniques or analysis techniques, both of which are used interchangeably herein) which can be selected based on the tracking system used. [0894] In some embodiments, the targeting systems described herein is detected utilizing a nuclear imaging technique. Nuclear imaging techniques, as used herein, are meant to encompass any imaging, detection, couniting, or sorting technique that utilizes radioactive emissions, ether emitted from the subject or an external source. Without limitation, nuclear imaging techniques may include X-ray, magnetic resonance imaging (MRI) including functional magnetic resonance imaging (fMRI) and nuclear magnetic resonance imaging, computed tomography (CT), positron emission tomography (PET), single-photon emission computed tomography (SPECT), absorption imaging, or any combination thereof. The general principles and procedures of these approaches are known in the art, see Pérez-Medina, et. al., Nuclear imaging approaches facilitating nanomedicine translation. Advanced Drug Delivery Reviews 154–155 (2020) 123–141, the contents of which are herein incorporated by reference in their entirety as it relates to nuclear imaging techniques. [0895] In some embodiments, detection of the targeting systems described herein in a subject may be performed utilizing MRI techniques. This approach may be carried out by any method known or discovered. While not wishing to be bound by theory, MRI utilizes the detection of certain nuclide spin characteristics. In some embodiments, MRI may be used as a non-invasive detection technique along with the targeting systems described herein that comprises an MRI contrast agent such as gadolinium-based small molecules, manganese-based small molecules, iron oxide nanoparticles, 19 F-based compounds, and any combination thereof. MRI techniques may, as an example, allow for a detection of the targeting systems in specific organs and tissues of a subject in vivo, as well as changes in those distributions over time. [0896] In some embodiments, detection of the targeting systems described herein in a subject may be performed utilizing CT techniques. This approach may be carried out by any method known or discovered. While not wishing to be bound by theory, CT utilizes the interaction of X-ray photons with matter, CT may be used as a non-invasive detection technique along with the targeting systems that comprise an CT contrast agent such as a gold high-density lipoprotein nanoparticle (Au-HDL). CT techniques may, as an example, allow for a detection of the targeting systems in specific organs and tissues of a subject in vivo, as well as changes in those distributions over time. [0897] In some embodiments, detection of the targeting systems described herein in a subject may be performed utilizing PET techniques. This approach may be carried out by any method known or discovered. While not wishing to be bound by theory, PET utilize detection of photon emission from exogenously administered radiological substances, i.e., radiotracers. Principally, PET scanners detect the two photons emitted in opposite directions after positron-electron annihilation (the coincidence event). PET may be used as either an invasive or non-invasive detection technique along with the targeting systems that comprise an appropriate radiolabel such as 111In, 99mTc, 13N, 68Ga, 18F, 64Cu, 86Y, 76Br, 89Zr, 72As, 124I, 74As, fluorine- 18, gallium-68, nitrogen-13, copper-64, bromine-76, iodine-125, arsenic-74, carbon-11, iodine-131, 153Sm, 177Lu, 186Re, 188Re, 198Au, and 225Ac. These labels may be conjugated to either the structural elements, the cargo components, or both. PET scans may be performed to detect distribution of the targeting systems either on the subject in vivo, including changes in those distributions over time, or on excised samples of the subject. PET techniques may allow for detection of the targeting systems in a subject from the organ/tissue level down to the cell type level. Some PET techniques may allow for detection of the targeting systems at the intracellular level. [0898] In some embodiments, detection of the targeting systems described herein in a subject may be performed utilizing SPECT techniques. This approach may be carried out by any method known or discovered. While not wishing to be bound by theory, SPECT utilize detection of photon emission from exogenously administered radiological substances, i.e., radiotracers. Principally, SPECT scanners detect X-ray and gamma photons associated with nuclear state transitions. SPECT may be used as either an invasive or non-invasive detection technique along with the targeting systems that comprise an appropriate radiolabel such as 111In, 99mTc, 13N, 68Ga, 18F, 64Cu, 86Y, 76Br, 89Zr, 72As, 124I, 74As, fluorine-18, gallium-68, nitrogen-13, copper-64, bromine-76, iodine-125, arsenic-74, carbon-11, iodine- 131, 153Sm, 177Lu, 186Re, 188Re, 198Au, and 225Ac. These labels may be conjugated to either the structural elements, the cargo components, or both. SPECT scans may be performed to detect distribution of the targeting systems either on the subject in vivo, including changes in those distributions over time, or on excised samples of the subject. SPECT techniques may allow for detection of the targeting systems in a subject from the organ/tissue level down to the cell type level. Some SPECT techniques may allow for detection of the targeting systems at the intracellular level. [0899] In some embodiments, multiple nuclear imaging techniques may be used with the targeting systems comprising a single tracking system. In some embodiments, multiple nuclear imaging techniques may be used with the targeting systems comprising multiple tracking systems. [0900] In some embodiments, the targeting systems described herein is detected utilizing an optical imaging technique. Optical imaging techniques, as used herein, are meant to encompass any imaging, detection, couniting, or sorting technique that utilizes light emissions and the special properties of photons, ether emitted from the subject or an external source. Without limitation, optical imaging techniques may include visible light microscopy, Raman spectroscopy, fluorescence microscopy, bioluminescence imaging (BLI), optical coherence tomography, or any combination thereof. The general principles and procedures of these approaches are known in the art, see Drummen. Fluorescent Probes and Fluorescence (Microscopy) Techniques — Illuminating Biological and Biomedical Research. Molecules 2012, 17, 14067-14090, Boutorine, et. al., Fluorescent Probes for Nucleic Acid Visualization in Fixed and Live Cells. Molecules 2013, 18, 15357-15397, and Juskowiak, Nucleic acid-based fluorescent probes and their analytical potential. Anal. Bioanal. Chem. (2011) 399:3157– 3176, the contents of which are herein incorporated by reference in their entirety as relates to optical imaging techniques. [0901] In some embodiments, detection of the targeting systems described herein in a subject may be performed utilizing visible fluorescence microscopy techniques. Fluorescence microscopy techniques include a wide range of techniques known in the art including without limitation confocal fluorescence microscopy, fluorescence reflectance imaging, fluorescence molecular tomographic imaging, and Förster Resonance Energy Transfer (FRET). In general, all fluorescence microscopy techniques utilize detection of light emitted from endogenously present or exogenously administered fluorescent compounds, i.e., compounds which absorb light or other electromagnetic radiation and re-emits it at longer wavelengths. Fluorescence microscopy techniques may be used as either an invasive or non-invasive detection technique along with the targeting systems that comprise at least one tracking system which comprises an appropriate fluorescent compound. Without limitation, such fluorescent compounds may include Green Florescent Protein, Yellow Florescent Protein, Red Florescent Protein, Sirius, EBFP2, CFP, Cerulean, EGFP, EYFP, mOrange, mCherry, mPlum, NIR, iRFP, EosFP, PamCherry, Dronpa, Dreiklang, asFP595, mMaple, mGeo, mEos2, Dendra2, psCFP2, 2,3,5,6- tetracarbazole-4-cyano-pyridine (CPy), florescent nanoparticles, or florescent lipids, fluorescein, TAMRA, Cy dyes, Texas red, HEX, JOE, Oregon green, rhodamine 6 G, coumarin, pyrene, DiOC6 (3,3′-dihexyloxacarbocyanine iodide), or any combination thereof. In some embodiments, a targeting system for detection with fluorescence microscopy will comprise at least one fluorophore which may include, without limitation, a quantum dot, a Coumarins, a Naphthalimide, a Fluorescein, a BODIPY, a Cyanine, a xanthene, an oxazine, an Oligothiophenes, and a Phthalocyanine derivative (PcDer). These fluorescence compounds may be incorporated into the structure of the targeting systems, loaded as a cargo or payload, expressed as the product of a cargo or payload, or any combination thereof. Fluorescence microscopy techniques may be performed to detect distribution of the targeting systems either on the subject in vivo, including changes in those distributions over time, or on excised samples of the subject. Fluorescence microscopy techniques may allow for detection of the targeting systems in a subject from the organ/tissue level down to the cell type level. Some fluorescence microscopy techniques may allow for detection of the targeting systems at the intracellular level. In some embodiments, fluorescence microscopy techniques may be used to sort samples of cells post administration utilizing Fluorescence-activated Cell Sorting (FACS). [0902] In some embodiments, detection of the targeting systems in a subject may be performed utilizing bioluminescence imaging (BLI) techniques. This approach may be carried out by any method known or discovered. While not wishing to be bound by theory, BLI imaging utilizes exogenously supplied compounds which emit light as a product of a chemical reaction under physiological condition. These emissions may be detected through various techniques of light and fluorescence microscopy. In some embodiments, BLI techniques may be used in conjunction with targeting systems which comprise bioluminescent compounds. Such compounds may be incorporated into nanoparticles or as the cargo or payload for expression post-delivery. In some embodiments, bioluminescent compounds may include, but are not limited to, luciferases including Renilla luciferase, Gaussia luciferase, Nanoluc luciferase, Firefly luciferase, Click Beetle luciferases, or any combination thereof. BLI techniques may be performed to detect distribution of the tropism discovery platform either on the subject in vivo, including changes in those distributions over time, or on excised samples of the subject. BLI may allow for detection of the targeting systems in a subject from the organ/tissue level down to the cell type level. Some BLI techniques may allow for detection of the targeting systems at the intracellular level. In some embodiments, BLI techniques may include quantifying luciferase expression from different organs with an in vivo imaging system (IVIS). [0903] In some embodiments, detection of the targeting systems described herein may be performed utilizing nucleotide sequencing techniques. Nucleotide sequencing techniques maybe used to detect the presence of a known sequence of nucleotides, such as an identifier (e.g., barcode) sequence, in a sample. Non-limiting examples of nucleotide sequencing techniques which may be used to detect the targeting systems include high throughput sequencing, PCR, deep sequencing, and any combination thereof. [0904] In some embodiments, detection of the targeting systems described herein may be performed by detecting the product of a tracking system which comprises a functional polynucleotide (e.g., DNA, mRNA, or oRNA) coding for a known peptide sequence or protein (i.e., a reporter sequence). In some embodiments, the functional polynucleotide may comprise a sequence which codes for a unique non-functional polypeptide sequence (i.e., a peptide or protein). In some embodiments, the reporter sequence may comprise a β-galactosidase (β-gal) sequence. In some embodiments, the reporter sequence may comprise a eGFP, luciferase, gene editor (e.g. cas9 edit, DNA readout), ox-40, beta6 integrin, CD45, a surface marker with (3x)- HA tag, (3x)-flag tag (with or without) a TEV protease site, or any combination thereof. In some embodiments, the reporter sequence may comprise a luciferase or fluorescent compound sequence. In some embodiments, the expression of the functional sequence, and by extension the presence of the targeting systems may be performed by any technique disclosed previously. In some embodiments, detecting the product of a tracking system which comprises a reporter sequence may be performed using any method known or discovered to detect products of expression. Such techniques include, but are not limited to, liquid/gas chromatography, mass spectrometry, light spectrometry (absorbance), gel electrophoresis, quantitative enzyme-linked immunosorbent assays (ELISA), Western blotting, dot blotting, Northern Blotting, protein immunostaining, protein immunoprecipitation, or any combination thereof. [0905] In some embodiments, detection of the targeting systems described herein may be performed by utilizing detections systems chosen to match especially designed tracking systems. As a non-limiting example, the targeting systems described herein may be detected by electron microscopy, thermal imaging, ultrasound imaging, photoacoustic imaging, lab assays, and any combination thereof. [0906] In some embodiments, detection of the targeting systems described herein may be performed by utilizing cell sorting techniques, including but not limited to, magnetic beads, flow cytometry, cleavage of peptide with LC-MS/MS, Fluorescence-activated Cell Sorting (FACS), or any combination thereof, combined with tracking system nanoparticles comprising components recognized by the cell sorting method. [0907] In some embodiments, a detection technique may analyze only one formulation or cargo at a time. In some embodiments, a detection technique may analyze multiple formulations or cargos at a time. In some embodiments, a detection technique may analyze about 1 formulation, 2 formulations, 3 formulations, 4 formulations 5, formulations, 6 formulations, 7, formulations, 8, formulations, 9 formulations, 10 formulations, 11 formulations, 12 formulations, 13 formulations, 14 formulations, 15 formulations, 16 formulations, 17 formulations, 18 formulations, 19 formulations, 20 formulations, 21 formulations, 22 formulations, 23 formulations, 24 formulations, 25 formulations, or more at a time. In some embodiments, a detection technique may analyze between about 1 and 100 formulations. As a non-limiting example, a detection technique may analyze about 1-10, 1-20, 1-30, 1-40.1-50, 1-60, 1-70.1- 80, or 1-90 formulations. In some embodiments, a detection technique may analyze more than 100 formulations at a time. [0908] In some embodiments, a library of targeting systems may be analyzed. As a non- limiting examples, targeting systems may have the same formulation and different identifier sequences or moieties. As another non-limiting example, targeting systems may have the same formulation and the same identifier sequences or moieties. As another non-limiting example, targeting systems may have different formulations and the same identifier sequence or moieties. As another non-limiting example, targeting systems may have different formulations and different identifier sequences of moieties. [0909] In some embodiments, a library of targeting systems may have one identifier sequence or moiety for analysis. [0910] In some embodiments, a library of targeting systems may have at least two identifier sequences or moieties for analysis. The library may have 2-10 identifier sequences or moieties for analysis. The library may have 2-100 identifier sequences or moieties for analysis. The library may have 2-500 identifier sequences or moieties for analysis. The library may have 100-500 identifier sequences or moieties for analysis. The library may have 2-1000 identifier sequences or moieties for analysis. The library may have 2-2500 identifier sequences or moieties for analysis. The library may have 1000-2500 identifier sequences or moieties for analysis. The library may have 1000-5000 identifier sequences or moieties for analysis. The library may have 2500-5000 identifier sequences or moieties for analysis. The library may have 4000-5000 identifier sequences or moieties for analysis. [0911] In some embodiments, a library of targeting systems may have at least one originator constructs or benchmark constructs formulated in a nanoparticle delivery vehicle. The library may have 1-10000 nanoparticles. The library may have 1-10 nanoparticles. The library may have 1-100 nanoparticles. The library may have 1-500 nanoparticles. The library may have 100-500 nanoparticles. The library may have 1-1000 nanoparticles. The library may have 100- 500 nanoparticles. The library may have 1000-5000 nanoparticles. The library may have 2500- 5000 nanoparticles. The library may have 1-5000 nanoparticles. The library may have 1-10000 nanoparticles. The library may have 5000-10000 nanoparticles. As a non-limiting example, the nanoparticle may be a lipid nanoparticle. VIII. METHODS OF USE [0912] In some embodiments, the tropism delivery systems described herein may be used as a therapeutic to diagnose, prevent, treat and/or manage disease, disorders and conditions, or as a diagnostic. The therapeutic may be used in personalized medicine, immuno-oncology, cancer, vaccines, gene editing (e.g., CRISPR). [0913] In some embodiments, the tropism delivery systems described herein may be used for diagnostic purposes or as diagnostic tools. [0914] In some emodibments, delivery systems described herein may be used to treat a foodborne illness, gastroentities, an infectious disease, a neglected topical disease, a tropical disease, a vector-borne disease, a toxin exposure, [0915] The pharmaceutical composition may be delivered as described in PCT Publication WO2012135805, which is incorporated herein by reference in its entirety. [0916] The present disclosure provides methods comprising administering a pharmaceutical composition to a subject in need thereof. The pharmaceutical composition may be administered to a subject using any amount and any route of administration which may be effective for preventing, treating, diagnosing, or imaging a disease, disorder, and/or condition. The exact amount required will vary from subject to subject, depending on factors such as, but not limited to, the species, age, and general condition of the subject, the severity of the disease, the particular composition, its mode of administration, its mode of activity, and the like. The pharmaceutical composition may be administered to animals, such as mammals (e.g., humans, domesticated animals, cats, dogs, monkeys, mice, rats, etc.). The payload of the pharmaceutical composition is a polynucelotide. [0917] In some embodiments, pharmaceutical, prophylactic, diagnostic, or imaging compositions thereof are administered to humans. [0918] In some embodiments, the active agent is administered by one or more of a variety of routes, including, but not limited to, local, oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (e.g., by powders, ointments, creams, gels, lotions, and/or drops), mucosal, nasal, buccal, enteral, vitreal, intratumoral, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; as an oral spray, nasal spray, and/or aerosol, and/or through a portal vein catheter. [0919] In some embodiments, the active agent is administered by systemic intravenous injection. [0920] In some embodiments, the active agent is administered intravenously and/or orally. [0921] In specific embodiments, the active agent may be administered in a way which allows the active agent to cross the blood-brain barrier, vascular barrier, or other epithelial barrier. [0922] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing agents, wetting agents, and/or suspending agents. Sterile injectable preparations may be sterile injectable solutions, suspensions, and/or emulsions in nontoxic parenterally acceptable diluents and/or solvents, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid can be used in the preparation of injectables. [0923] Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, and/or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [0924] Dosage forms for local, topical and/or transdermal administration of a pharmaceutical composition may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms may be prepared, for example, by dissolving and/or dispensing the compound in the proper medium. Alternatively or additionally, rate may be controlled by either providing a rate controlling membrane and/or by dispersing the compound in a polymer matrix and/or gel. [0925] Formulations suitable for topical administration include, but are not limited to, liquid and/or semi liquid preparations such as liniments, lotions, oil in water and/or water in oil emulsions such as creams, ointments and/or pastes, and/or solutions and/or suspensions. Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein. [0926] A pharmaceutical composition may be prepared, packaged, and/or sold in a formulation suitable for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1/1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of any additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this disclosure. [0927] In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the active agent to be delivered (e.g., its stability in the environment of the gastrointestinal tract, bloodstream, etc), the condition of the patient (e.g., whether the patient is able to tolerate particular routes of administration), etc. The present disclosure encompasses the delivery of the active agent by any appropriate route taking into consideration likely advances in the sciences of drug delivery. [0928] In certain embodiments, pharmaceutical compositions in accordance with the present disclosure may be administered at dosage levels sufficient to deliver from about 0.0001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, or from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic, diagnostic or prophylactic effect. The desired dosage may be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). When multiple administration is employed, split dosing regimens such as those described herein may be used. [0929] According to the present disclosure, administration of active agent in split-dose regimens may produce higher levels of proteins in mammalian subjects. As used herein, a “split dose” is the division of single unit dose or total daily dose into two or more doses. As used herein, a “single unit dose” is a dose of any therapeutic administered in one dose/at one time/single route/single point of contact, i.e., single administration event. As used herein, a “total daily dose” is an amount given or prescribed in 24 hr period. It may be administered as a single unit dose. In one embodiment, the active agent of the present disclosure are administered to a subject in split doses. In some embodiments, the active agent is formulated in buffer only or in a formulation described herein. [0930] LNPs of the present disclosure may be used or administered in combination with one or more other therapeutic, prophylactic, diagnostic, or imaging agents. By “in combination with,” it is not intended to imply that the agents must be administered at the same time and/or formulated for delivery together, although these methods of delivery are within the scope of the present disclosure. Pharmaceutical compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. In general, each agent will be administered at a dose and/or on a time schedule determined for that agent. In some embodiments, the present disclosure encompasses the delivery of pharmaceutical, prophylactic, diagnostic, or imaging compositions in combination with agents that may improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body. [0931] It will further be appreciated that therapeutically, prophylactically, diagnostically, or imaging active agents utilized in combination may be administered together in a single pharmaceutical composition or administered separately in different pharmaceutical compositions. In general, it is expected that agents utilized in combination with be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually. In one embodiment, the combinations, each or together may be administered according to the split dosing regimens described herein. [0932] The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, a pharmaceutical composition useful for treating cancer in accordance with the present disclosure may be administered concurrently with a chemotherapeutic agent), or they may achieve different effects (e.g., control of any adverse effects). [0933] Pharmaceutical compositions containing LNPs disclosed herein are formulated for administration intramuscularly, transarterially, intraocularly, vaginally, rectally, intraperitoneally, intravenously, intranasally, subcutaneously, endoscopically, transdermally, intramuscularly, intraventricularly, intradermally, intrathecally, topically (e.g. by powders, ointments, creams, gels, lotions, and/or drops), mucosally, nasal, enterally, intratumorally, by intratracheal instillation, bronchial instillation, and/or inhalation; nasal spray and/or aerosol, and/or through a portal vein catheter. [0934] The pharmaceutical compositions may also be formulated for direct delivery to an organ or tissue in any of several ways in the art including, but not limited to, direct soaking or bathing, via a catheter, by gels, powder, ointments, creams, gels, lotions, and/or drops, by using substrates such as fabric or biodegradable materials coated or impregnated with the pharmaceutical compositions, and the like. In some embodiments, the pharmaceutical composition is formulated for extended release. In specific embodiments, the active agent and/or pharmaceutical, prophylactic, diagnostic, or imaging compositions thereof, may be administered in a way which allows the active agent to cross the blood-brain barrier, vascular barrier, or other epithelial barrier. [0935] In some aspects of the present disclosure, the active agent of the present disclosure are spatially retained within or proximal to a target tissue. Provided are methods of providing a pharmaceutical composition to a target tissue of a mammalian subject by contacting the target tissue (which contains one or more target cells) with the pharmaceutical composition under conditions such that the pharmaceutical composition, in particular the active agent component(s) of the pharmaceutical composition, is substantially retained in the target tissue, meaning that at least 10, 20, 30, 40, 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, 99.99 or greater than 99.99% of the pharmaceutical composition is retained in the target tissue. Advantageously, retention is determined by measuring the amount of a component of the active agent present in the pharmaceutical composition that enters one or more target cells. For example, at least 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, 99.99 or greater than 99.99% of the active agent administered to the subject are present intracellularly at a period of time following administration. [0936] Aspects of the present disclosure are directed to methods of providing a pharmaceutical composition to a target tissue or organ of a mammalian subject, by contacting the target tissue (containing one or more target cells) or organ (containing one or more target cells) with the pharmaceutical composition under conditions such that the pharmaceutical composition is substantially retained in the target tissue or organ. The pharmaceutical composition contains an effective amount of an active agent. [0937] Pharmaceutical compositions which may be administered intramuscularly and/or subcutaneously may include, but are not limited to, polymers, copolymers, and gels. The polymers, copolymers and/or gels may further be adjusted to modify release kinetics by adjusting factors such as, but not limited to, molecular weight, particle size, payload and/or ratio of the monomers. As a nonlimiting example, formulations administered intramuscularly and/or subcutaneously may include a copolymer such as poly(lactic-co-glycolic acid). [0938] Localized delivery of the pharmaceutical compositions described herein may be administered by methods such as, but not limited to, topical delivery, ocular delivery, transdermal delivery, and the like. The pharmaceutical composition may also be administered locally to a part of the body not normally available for localized delivery such as, but not limited to, when a subject’s body is open to the environment during treatment. The pharmaceutical composition may further be delivered by bathing, soaking and/or surrounding the body part with the pharmaceutical composition. [0939] However, the present disclosure encompasses the delivery of an active agent disclosed herein, and/or pharmaceutical, prophylactic, diagnostic, or imaging compositions thereof, by any appropriate route taking into consideration likely advances in the sciences of drug delivery. Methods of Producing Polypeptides in Cells [0940] The present disclosure provides methods of producing a polypeptide of interest in a mammalian cell. Methods of producing polypeptides involve contacting a cell with a formulation of the disclosure comprising an LNP including an mRNA encoding the polypeptide of interest. Upon contacting the cell with the lipid nanoparticle, the mRNA may be taken up and translated in the cell to produce the polypeptide of interest. [0941] In general, the step of contacting a mammalian cell with a LNP including an mRNA encoding a polypeptide of interest may be performed in vivo, ex vivo, in culture, or in vitro. The amount of lipid nanoparticle contacted with a cell, and/or the amount of mRNA therein, may depend on the type of cell or tissue being contacted, the means of administration, the physiochemical characteristics of the lipid nanoparticle and the mRNA (e.g., size, charge, and chemical composition) therein, and other factors. In general, an effective amount of the lipid nanoparticle will allow for efficient polypeptide production in the cell. Metrics for efficiency may include polypeptide translation (indicated by polypeptide expression), level of mRNA degradation, and immune response indicators. [0942] The step of contacting an LNP including an mRNA with a cell may involve or cause transfection. A phospholipid including in the lipid component of a LNP may facilitate transfection and/or increase transfection efficiency, for example, by interacting and/or fusing with a cellular or intracellular membrane. Transfection may allow for the translation of the mRNA within the cell. [0943] In some embodiments, the lipid nanoparticles described herein may be used therapeutically. For example, an mRNA included in an LNP may encode a therapeutic polypeptide (e.g., in a translatable region) and produce the therapeutic polypeptide upon contacting and/or entry (e.g., transfection) into a cell. In other embodiments, an mRNA included in a LNP may encode a polypeptide that may improve or increase the immunity of a subject. In some embodiments, an mRNA may encode a granulocyte-colony stimulating factor or trastuzumab. [0944] In some embodiments, an mRNA included in an LNP may encode a recombinant polypeptide that may replace one or more polypeptides that may be substantially absent in a cell contacted with the lipid nanoparticle. The one or more substantially absent polypeptides may be lacking due to a genetic mutation of the encoding gene or a regulatory pathway thereof. Alternatively, a recombinant polypeptide produced by translation of the mRNA may antagonize the activity of an endogenous protein present in, on the surface of, or secreted from the cell. An antagonistic recombinant polypeptide may be desirable to combat deleterious effects caused by activities of the endogenous protein, such as altered activities or localization caused by mutation. In another alternative, a recombinant polypeptide produced by translation of the mRNA may indirectly or directly antagonize the activity of a biological moiety present in, on the surface of, or secreted from the cell. Antagonized biological moieties may include, but are not limited to, lipids (e.g., cholesterol), lipoproteins (e.g., low density lipoprotein), nucleic acids, carbohydrates, and small molecule toxins. Recombinant polypeptides produced by translation of the mRNA may be engineered for localization within the cell, such as within a specific compartment such as the nucleus, or may be engineered for secretion from the cell or for translocation to the plasma membrane of the cell. [0945] In some embodiments, contacting a cell with an LNP including an mRNA may reduce the innate immune response of a cell to an exogenous nucleic acid. A cell may be contacted with a first lipid nanoparticle including a first amount of a first exogenous mRNA including a translatable region and the level of the innate immune response of the cell to the first exogenous mRNA may be determined. Subsequently, the cell may be contacted with a second composition including a second amount of the first exogenous mRNA, the second amount being a lesser amount of the first exogenous mRNA compared to the first amount. Alternatively, the second composition may include a first amount of a second exogenous mRNA that is different from the first exogenous mRNA. The steps of contacting the cell with the first and second compositions may be repeated one or more times. Additionally, efficiency of polypeptide production (e.g., translation) in the cell may be optionally determined, and the cell may be re-contacted with the first and/or second composition repeatedly until a target protein production efficiency is achieved. Methods of Delivering Therapeutic Agents to Cells and Organs [0946] Provided herein are methods of treating a disease or disorder, the methods comprising administering to a subject in need thereof a pharmaceutical composition of the present disclosure, such as a pharmaceutical composition comprising an LNP described herein. [0947] The present disclosure provides methods of delivering an active agent and/or prophylactic, such as a nucleic acid, to a mammalian cell or organ. Delivery of a therapeutic and/or prophylactic to a cell involves administering a formulation of the disclosure that comprises a LNP including the therapeutic and/or prophylactic, such as a nucleic acid, to a subject, where administration of the composition involves contacting the cell with the composition. In some embodiments, a protein, cytotoxic agent, radioactive ion, chemotherapeutic agent, or nucleic acid (such as an RNA, e.g., mRNA) may be delivered to a cell or organ. In the instance that a therapeutic and/or prophylactic is an mRNA, upon contacting a cell with the lipid nanoparticle, a translatable mRNA may be translated in the cell to produce a polypeptide of interest. However, mRNAs that are substantially not translatable may also be delivered to cells. Substantially non-translatable mRNAs may be useful as vaccines and/or may sequester translational components of a cell to reduce expression of other species in the cell. [0948] In some embodiments, an LNP may target a particular type or class of cells (e.g., cells of a particular organ or system thereof). In some embodiments, a LNP including a therapeutic and/or prophylactic of interest may be specifically delivered to a mammalian liver, kidney, spleen, femur, or lung. “Specific delivery” to a particular class of cells, an organ, or a system or group thereof implies that a higher proportion of lipid nanoparticles including a therapeutic and/or prophylactic are delivered to the destination (e.g., tissue) of interest relative to other destinations, e.g., upon administration of an LNP to a mammal. In some embodiments, specific delivery may result in a greater than 2 fold, 5 fold, 10 fold, 15 fold, or 20 fold increase in the amount of therapeutic and/or prophylactic per 1 g of tissue of the targeted destination (e.g., tissue of interest, such as a liver) as compared to another destination (e.g., the spleen). In some embodiments, the tissue of interest is selected from the group consisting of a liver, kidney, a lung, a spleen, a femur, vascular endothelium in vessels (e.g., intra-coronary or intra-femoral) or kidney, and tumor tissue (e.g., via intratumoral injection). [0949] As another example of targeted or specific delivery, an mRNA that encodes a protein- binding partner (e.g., an antibody or functional fragment thereof, a scaffold protein, or a peptide) or a receptor on a cell surface may be included in an LNP. An mRNA may additionally or instead be used to direct the synthesis and extracellular localization of lipids, carbohydrates, or other biological moieties. Alternatively, other therapeutics and/or prophylactics or elements (e.g., lipids or ligands) of an LNP may be selected based on their affinity for particular receptors (e.g., low density lipoprotein receptors) such that a LNP may more readily interact with a target cell population including the receptors. In some embodiments, ligands may include, but are not limited to, members of a specific binding pair, antibodies, monoclonal antibodies, Fv fragments, single chain Fv (scFv) fragments, Fab' fragments, F(ab')2 fragments, single domain antibodies, camelized antibodies and fragments thereof, humanized antibodies and fragments thereof, and multivalent versions thereof; multivalent binding reagents including mono- or bi- specific antibodies such as disulfide stabilized Fv fragments, scFv tandems, diabodies, tribodies, or tetrabodies; and aptamers, receptors, and fusion proteins. [0950] In some embodiments, a ligand may be a surface-bound antibody, which can permit tuning of cell targeting specificity. This is especially useful since highly specific antibodies can be raised against an epitope of interest for the desired targeting site. In some embodiments, multiple antibodies are expressed on the surface of a cell, and each antibody can have a different specificity for a desired target. Such approaches can increase the avidity and specificity of targeting interactions. [0951] A ligand can be selected, e.g., by a person skilled in the biological arts, based on the desired localization or function of the cell. In some embodiments an estrogen receptor ligand, such as tamoxifen, can target cells to estrogen-dependent breast cancer cells that have an increased number of estrogen receptors on the cell surface. Other non-limiting examples of ligand/receptor interactions include CCR1 (e.g., for treatment of inflamed joint tissues or brain in rheumatoid arthritis, and/or multiple sclerosis), CCR7, CCR8 (e.g., targeting to lymph node tissue), CCR6, CCR9, CCR10 (e.g., to target to intestinal tissue), CCR4, CCR10 (e.g., for targeting to skin), CXCR4 (e.g., for general enhanced transmigration), HCELL (e.g., for treatment of inflammation and inflammatory disorders, bone marrow), Alpha4beta7 (e.g., for intestinal mucosa targeting), and VLA-4NCAM-1 (e.g., targeting to endothelium). In general, any receptor involved in targeting (e.g., cancer metastasis) can be harnessed for use in the methods and compositions described herein. [0952] Targeted cells may include, but are not limited to, hepatocytes, epithelial cells, hematopoietic cells, epithelial cells, endothelial cells, lung cells, bone cells, stem cells, mesenchymal cells, neural cells, cardiac cells, adipocytes, vascular smooth muscle cells, cardiomyocytes, skeletal muscle cells, beta cells, pituitary cells, synovial lining cells, ovarian cells, testicular cells, fibroblasts, B cells, T cells, reticulocytes, leukocytes, granulocytes, and tumor cells. [0953] In some embodiments, an LNP may target hepatocytes. Apolipoproteins such as apolipoprotein E (apoE) have been shown to associate with neutral or near neutral lipid- containing lipid nanoparticles in the body, and are known to associate with receptors such as low-density lipoprotein receptors (LDLRs) found on the surface of hepatocytes. Thus, an LNP including a lipid component with a neutral or near neutral charge that is administered to a subject may acquire apoE in a subject's body and may subsequently deliver a therapeutic and/or prophylactic (e.g., an RNA) to hepatocytes including LDLRs in a targeted manner. Methods of Treating Diseases and Disorders [0954] Lipid nanoparticles are useful for treating a disease, disorder, or condition. In particular, such compositions are useful in treating a disease, disorder, or condition characterized by missing or aberrant protein or polypeptide activity. In some embodiments, a formulation of the disclosure that comprises an LNP including an mRNA encoding a missing or aberrant polypeptide may be administered or delivered to a cell. Subsequent translation of the mRNA may produce the polypeptide, thereby reducing or eliminating an issue caused by the absence of or aberrant activity caused by the polypeptide. Because translation may occur rapidly, the methods and compositions may be useful in the treatment of acute diseases, disorders, or conditions such as sepsis, stroke, and myocardial infarction. A therapeutic and/or prophylactic included in an LNP may also be capable of altering the rate of transcription of a given species, thereby affecting gene expression. [0955] Diseases, disorders, and/or conditions characterized by dysfunctional or aberrant protein or polypeptide activity for which a composition may be administered include, but are not limited to, rare diseases, infectious diseases (as both vaccines and therapeutics), cancer and proliferative diseases, genetic diseases (e.g., cystic fibrosis), autoimmune diseases, diabetes, neurodegenerative diseases, cardio- and reno-vascular diseases, and metabolic diseases. Multiple diseases, disorders, and/or conditions may be characterized by missing (or substantially diminished such that proper protein function does not occur) protein activity. Such proteins may not be present, or they may be essentially non-functional. A specific example of a dysfunctional protein is the missense mutation variants of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which produce a dysfunctional protein variant of CFTR protein, which causes cystic fibrosis. The present disclosure provides a method for treating such diseases, disorders, and/or conditions in a subject by administering a LNP including an RNA and a lipid component including a PEGylated lipid compound disclosed herein, a phospholipid (optionally unsaturated), optionally a second PEGylated lipid, and a structural lipid, wherein the RNA may be an mRNA encoding a polypeptide that antagonizes or otherwise overcomes an aberrant protein activity present in the cell of the subject. [0956] In some embodiments, lipid nanoparticles disclosed herein comprise a polynucleotide encoding an antigen protein. In some embodiments, a polynucleotide is an mRNA or circRNA encoding an antigen protein. In some embodiments, a polynucleotide encodes a protein selected from SEQ ID NOs: 1-54, or a sequence having about 60% sequence identity, about 70% sequence identity, about 80% sequence identity, about 90% sequence identity, or about 95% sequence identity to a protein selected from SEQ ID NOs: 1-54. [0957] In some embodiments, lipid nanoparticles disclosed herein a useful in method of treating a disease or disorder. In some embodiments, a disease or disorder is a foodbourne illness or gastroenteristis. In some embodiments, a foodbourne illness is caused by a pathogen selected from the group consisitng of Campylobacter jejuni bacteria, Clostridium difficile bacteria, Entamoeba histolytica, Enterotoxin B, Norwalk virus/Norovirus, Helicobacter pyroli, and Rotavirus. [0958] In some embodiments, a disease or disorder is an infectious disease. In some embodiments, an infectious agent is the result of an infection with an agent selected from the group consisting of candida yeast, a coronavirus (e.g., SARS-CoV, SARS-CoV-2, MERS- CoV), enterovirus 71, Epstein-Barr virus, Gram-Negative Bacteria (e.g., Bordetella), Gram- Positive bacteria (e.g., Clostridium Tetani, Francisella tularensis, Streptococcus bacteria, Staphylococcus bacteria), hepatitis virus, human cytomegalovirus, HIV, HPV, influenza virus, JCV, mycobacterium, poxviruses, pseudomonos aeruginosa, toxoplasma gondii, vaicella zoster virus, chikungunya virus, dengue virus, rabies virus, typanosoma cruzi, ebola virus, plasmodium falciparum, marbug virus, Japanese encephalitis virus, St. Louis encephalitis virus, West Nile Virus, and Yellow Fever virus. Preventative Applications [0959] In some embodiments, the tropism delivery systems described herein may be used to prevent disease or stabilize the progression of disease. [0960] In some embodiments, the tropism delivery systems described herein may be used as a prophylactic to prevent a disease or disorder in the future. [0961] In some embodiments, the tropism delivery systems described herein may be used to halt further progression of a disease or disorder. Vaccine [0962] In some embodiments, the tropism delivery systems described herein may be used as, and/or in a manner similar to that of a vaccine. As used herein, a "vaccine" is a biological preparation that improves immunity to a particular disease or infectious agent. [0963] In some embodiments, the tropism delivery systems described herein may be used as, and/or in a manner similar to that of a vaccine for a therapeutic area such as, but not limited to, cardiovascular, CNS, dermatology, endocrinology, oncology, immunology, respiratory, and anti-infective. In some embodiments, the tropism delivery systems described herein may be used as a vaccine to diagnose, prevent, treat and/or manage a foodborne illness. In some embodiments, the tropism delivery systems described herein may be used as a vaccine to diagnose, prevent, treat and/or manage gastroenteritis. In some embodiments, the tropism delivery systems described herein may be used as a vaccine to diagnose, prevent, treat and/or manage influenza. In some embodiments, the tropism delivery systems described herein may be used as a prophylactic to diagnose, prevent, treat and/or manage HIV. In some embodiments, the tropism delivery systems described herein may be used as a prophylactic to diagnose, prevent, treat and/or manage coronavirus. In some embodiments, the tropism delivery systems described herein may be used as a prophylactic to diagnose, prevent, treat and/or manage COVID-19. In some embodiments, the tropism delivery systems described herein may be used as a prophylactic to diagnose, prevent, treat and/or manage polio. In some embodiments, the tropism delivery systems described herein may be used as a prophylactic to diagnose, prevent, treat and/or manage tetanus. In some embodiments, the tropism delivery systems described herein may be used as a prophylactic to diagnose, prevent, treat and/or manage Hepatitis A. In some embodiments, the tropism delivery systems described herein may be used as a prophylactic to diagnose, prevent, treat and/or manage Hepatitis B. In some embodiments, the tropism delivery systems described herein may be used as a prophylactic to diagnose, prevent, treat and/or manage Hepatitis C. In some embodiments, the tropism delivery systems described herein may be used as a prophylactic to diagnose, prevent, treat and/or manage Rubella. In some embodiments, the tropism delivery systems described herein may be used as a prophylactic to diagnose, prevent, treat and/or manage Hib (Haemophilus influenzae type b). In some embodiments, the tropism delivery systems described herein may be used as a prophylactic to diagnose, prevent, treat and/or manage Measles. In some embodiments, the tropism delivery systems described herein may be used as a prophylactic to diagnose, prevent, treat and/or manage Pertussis (Whooping Cough). In some embodiments, the tropism delivery systems described herein may be used as a prophylactic to diagnose, prevent, treat and/or manage Pneumococcal Disease. In some embodiments, the tropism delivery systems described herein may be used as a prophylactic to diagnose, prevent, treat and/or manage Rotavirus. In some embodiments, the tropism delivery systems described herein may be used as a prophylactic to diagnose, prevent, treat and/or manage Mumps. In some embodiments, the tropism delivery systems described herein may be used as a prophylactic to diagnose, prevent, treat and/or manage Chickenpox. In some embodiments, the tropism delivery systems described herein may be used as a prophylactic to diagnose, prevent, treat and/or manage Diphtheria. Contraceptive [0964] In some embodiments, the tropism delivery systems described herein may be used as, and/or in a manner similar to that of a contraceptive. As used herein, the term, "contraceptive" may be defined as any agent or method that may be used to prevent pregnancy. [0965] In some embodiments, the contraceptive may be used short-term or long-term. [0966] In some embodiments, the contraceptive may be reversible or permanent. Diagnostics [0967] In some embodiments, the tropism delivery systems described herein may be used for diagnostic purposes or as diagnostic tools for any of the aforementioned diseases or disorders. [0968] In some embodiments, the tropism delivery systems described herein may be used to detect a biomarker for disease diagnosis. [0969] In some embodiments, the tropism delivery systems described herein may be used for diagnostic imaging purposes, e.g., MRI, PET, CT or ultrasound. Research [0970] In some embodiments, the tropism delivery systems described herein may be used for diagnostic purposes or as research tools for any of the aforementioned diseases or disorders. [0971] In some embodiments, the tropism delivery systems described herein may be used to detect a biomarker for research. [0972] In some embodiments, the tropism delivery systems described herein may be used in any research experiment, e.g., in vivo or in vitro experiments. [0973] In some embodiments, the tropism delivery systems described herein may be used in cultured cells. The cultured cells may be derived from any origin known to one with skill in the art, and may be as non-limiting examples, derived from a stable cell line, an animal model or a human patient or control subject. [0974] In some embodiments, the tropism delivery systems described herein may be used in in vivo experiments in animal models (i.e., mouse, rat, rabbit, dog, cat, non-human primate, guinea pig, ferret, c-elegans, drosophila, zebrafish, or any other animal used for research purposes, known in the art). [0975] In some embodiments, the tropism delivery systems described herein may be used in human research experiments or human clinical trials. [0976] In some embodiments, the tropism delivery systems described herein may be used in stem cells and/or cell differentiation IX. ENUMERATED EMBODIMENTS Enumerated Embodiments, Section A [0977] The present disclosure include the enumerated embodiments 1-172 listed within Section A: 1. A compound of Formula I: or a pharmaceutically acceptable salt or solvate thereof, wherein: A is selected from the group consisting of -N(R 1a )- and -C(R')-OC(=O)(R 8a )-; R 1a is -L 1 -R 1 ; L 1 is C 2 -C 6 alkylenyl; R 1 is selected from the group consisting of -OH, R 2a , R 2b , and R 2c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 3a , R 3b , and R 3c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 4a , R 4b , and R 4c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 5a , R 5b , and R 5c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 6a , R 6b , and R 6c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or R 6a and R 6b taken together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclo; and R 6c is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 7a , R 7b , and R 7c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or R 7a and R 7b taken together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclo; and R 7c is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R' is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 8a is - L 2 -R 8 ; L 2 is C 2 -C 6 alkylenyl; R 8 is -NR 9a R 9b ; R 9a and R 9b are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or R 9a and R 9b taken together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclo; Q 1 is C 1 -C 20 alkylenyl; W 1 is selected from the group consisting of -C(=O)O-, -OC(=O)-, -C(=O)N(R 12a )- , -N(R 12a )C(=O)-, -OC(=O)N(R 12a )-, - N(R 12a )C(=O)O-, and -OC(=O)O-; R 12a is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; X1 is C 1 -C 15 alkylenyl; or X 1 is a bond; Y 1 is selected from the group consisting of -(CH 2 ) m -, -O-, -S-, and -S-S-; m is 0, 1, 2, 3, 4, 5, or 6; Z 1 is selected from the group consisting of C 4 -C 12 cycloalkylenyl, R 10 is selected from the group consisting of hydrogen, C 1 -C 20 alkyl, and C 2 -C 20 alkenyl; Q 2 is C 1 -C 20 alkylenyl; W 2 is selected from the group consisting of -C(=O)O-, -C(=O)N(R 12b )-, - OC(=O)N(R 12b )-, and -OC(=O)O-; R 12b is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; X 2 is C 1 -C 15 alkylenyl; or X 2 is a bond; Y 2 is selected from the group consisting of -(CH 2 ) n -, -O-, -S-, and -S-S-; n is 0, 1, 2, 3, 4, 5, or 6; Z 2 is selected from the group consisting of -(CH 2 ) p -, C 4 -C 12 cycloalkylenyl, p is 0 or 1; and R 11 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, and C 2 -C 10 alkenyl; 2. The compound of embodiment 1 of Formula II: or a pharmaceutically acceptable salt or solvate thereof. 3. The compound of embodiment 2, or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is selected from the group consisting of -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - , and -CH 2 CH 2 CH 2 CH 2 -. 4. The compound of embodiment 2 or 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is R 1 -1. 5. The compound of embodiment 4, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2a , R 2b , and R 2c are independently selected from the group consisting of hydrogen and methyl. 6. The compound of embodiment 2 or 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is R 1 -2. 7. The compound of embodiment 6, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a , R 3b , and R 3c are independently selected from the group consisting of hydrogen and methyl. 8. The compound of embodiment 2 or 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is R 1 -3. 9. The compound of embodiment 8, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4a , R 4b , and R 4c are independently selected from the group consisting of hydrogen and methyl 10. The compound of embodiment 2 or 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is R 1 -4. 11. The compound of embodiment 4, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5a , R 5b , and R 5c are independently selected from the group consisting of hydrogen and methyl. 12. The compound of embodiment 2 or 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -OH. 13. The compound of embodiment 1 of Formula III: or a pharmaceutically acceptable salt or solvate thereof. 14. The compound of embodiment 13 of Formula IV: or a pharmaceutically acceptable salt or solvate thereof, wherein -Q 1 -W 1 -X 1 -Y 1 -Z 1 -R 10 is not the same as -Q 2 -W 2 -X 2 -Y 2 -Z 2 -R 11 . 15. The compound of embodiment 13 of Formula V: or a pharmaceutically acceptable salt or solvate thereof, wherein -Q 1 -W 1 -X 1 -Y 1 -Z 1 -R 10 is not the same as -Q 2 -W 2 -X 2 -Y 2 -Z 2 -R 11 . 16. The compound of any one of embodiments 13-15, or a pharmaceutically acceptable salt or solvate thereof, wherein L 2 is selected from the group consisting of -CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, and -CH 2 CH 2 CH 2 CH 2 -. 17. The compound of any one of embodiments 13-16, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl. 18. The compound of embodiment 17, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b are methyl. 19. The compound of any one of embodiments 13-18, or a pharmaceutically acceptable salt or solvate thereof, wherein R' is hydrogen. 20. The compound of any one of embodiments 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein Q1 is C2-C10 alkylenyl. 21. The compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein W 1 is selected from the group consisting of -C(=O)O- and -OC(=O)- . 22. The compound of any one of embodiments 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 is a bond. 23. The compound of any one of embodiments 1-22, or a pharmaceutically acceptable salt or solvate thereof, wherein Y 1 is -(CH 2 ) m -; and m is 1. 24. The compound of any one of embodiments 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 1 is a monocyclic C 4 -C 8 cycloalkylenyl. 25. The compound of any one of embodiments 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 1 is selected from the group consisting of: 26. The compound of any one of embodiments 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 1 is selected from the group consisting of: 27. The compound of any one of embodiments 1-26, or a pharmaceutically acceptable salt or solvate thereof, wherein R 10 is hydrogen. 28. The compound of any one of embodiments 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein Q 2 is C 2 -C 10 alkylenyl. 29. The compound of any one of embodiments 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein W 2 is selected from the group consisting of -C(=O)O- and -OC(=O)- . 30. The compound of any one of embodiments 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein X 2 is C 1 -C 6 alkylenyl; or X 2 is a bond. 31. The compound of any one of embodiments 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein Y 2 is selected from the group consisting of -(CH 2 ) m - and -S-. 32. The compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 2 is -(CH 2 ) p - and p is 0. 33. The compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is C 1 -C 10 alkyl. 34. The compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is C 2 -C 10 alkenyl. 35. The compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 2 is C 4 -C 12 cycloalkylenyl. 36. The compound of embodiment 35, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 2 is a monocyclic C 4 -C 8 cycloalkylenyl. 37. The compound of embodiment 35, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 2 is selected from the group consisting of: 38. The compound of embodiment 35, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 2 is selected from the group consisting of: 39. The compound of any one of embodiments 35-38, or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is hydrogen. 40. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, selected from any one of more of the compounds of Table 1. 41. A pharmaceutical composition comprising: (a) a polynucleotide encoding at least one protein of interest; and (b) a delivery vehicle comprising one or more compounds of any one of embodiments 1-40. 42. The pharmaceutical composition of embodiment 41, wherein the polynucleotides are DNA. 43. The pharmaceutical composition of embodiment 41, wherein the polynucleotides are RNA. 44. The pharmaceutical composition of embodiment 43, wherein the RNA are short interfering RNA (siRNA). 45. The pharmaceutical composition of embodiment 44, wherein the siRNA inhibits or suppresses the expression of a target of interest in a cell. 46. The pharmaceutical composition of embodiment 45, wherein the inhibition or suppression is about 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95% and 100%, or at least 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 20-80%, 20-90%, 20-95%, 20-100%, 30-40%, 30-50%, 30-60%, 30-70%, 30-80%, 30-90%, 30-95%, 30-100%, 40-50%, 40-60%, 40-70%, 40-80%, 40-90%, 40-95%, 40-100%, 50-60%, 50-70%, 50-80%, 50-90%, 50-95%, 50-100%, 60-70%, 60-80%, 60-90%, 60-95%, 60-100%, 70-80%, 70-90%, 70-95%, 70-100%, 80-90%, 80-95%, 80-100%, 90-95%, 90-100% or 95-100%. 47. The pharmaceutical composition of embodiments 42 or 43, wherein the polynucleotides are substantially circular. 48. The pharmaceutical composition of embodiment 47, wherein polynucleotide comprises an internal ribosome entry site (IRES) sequence that is operably linked to the sequence region. 49. The pharmaceutical composition of embodiment 48, wherein the IRES sequence comprises a sequence derived from picornavirus complementary DNA, encephalomyocarditis virus (EMCV) complementary DNA, poliovirus complementary DNA, or an Antennapedia gene from Drosophila melanogaster. 50. The pharmaceutical composition of embodiment 47, wherein the polynucleotide comprises a termination element, wherein the termination element comprises at least one stop codon. 51. The pharmaceutical composition of embodiment 47, wherein the polynucleotide comprises a regulatory element. 52. The pharmaceutical composition of any of embodiments 47-51, wherein the polynucleotide comprises at least one masking agent. 53. The pharmaceutical composition of any of embodiments 47-52, wherein the substantially circular polynucleotide is produced using in vitro transcription. 54. The pharmaceutical composition of any of embodiments 47-53, wherein the polynucleotide sequence region comprises a non-coding nucleic acid sequence. 55. The pharmaceutical composition of any of embodiments 47-53, wherein the polynucleotide sequence region comprises a coding nucleic acid sequence. 56. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Campylobacter jejuni. 57. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Clostridium difficile. 58. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Entamoeba histolytica. 59. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for enterotoxin B. 60. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Norwalk virus or norovirus. 61. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Helicobacter pylori. 62. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for rotavirus. 63. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for candida yeast. 64. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for coronavirus. 65. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for SARS-CoV. 66. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for SARS-CoV-2. 67. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for MERS-CoV. 68. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Enterovirus 71. 69. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Epstein-Barr virus. 70. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Gram-Negative Bacteria. 71. The pharmaceutical composition of embodiment 70, wherein the Gram-Negative Bacteria is Bordetella. 72. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Gram-Positive Bacteria. . The pharmaceutical composition of embodiment 72, wherein the Gram-Positive Bacteria is Clostridium tetani. 74. The pharmaceutical composition of embodiment 72, wherein the Gram-Positive Bacteria is Francisella tularensis. 75. The pharmaceutical composition of embodiment 72, wherein the Gram-Positive Bacteria is Streptococcus bacteria. 76. The pharmaceutical composition of embodiment 72, wherein the Gram-Positive Bacteria is Staphylococcus bacteria. 77. The pharmaceutical composition of embodiment 75, wherein the coding nucleic acid sequence encodes a protein of interest for Hepatitis. 78. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Human Cytomegalovirus. 79. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Human Immunodeficiency Virus. 80. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Human Papilloma Virus. 81. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Influenza. 82. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for John Cunningham Virus. 83. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Mycobacterium. 84. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Poxviruses. 85. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Pseudomonas aeruginosa. 86. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Respiratory Syncytial Virus. 87. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Rubella virus. 88. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Varicella zoster virus. 89. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Chikungunya virus. 90. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Dengue virus. 91. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Rabies virus. 92. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Trypanosoma cruzi and/or Chagas disease. 93. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Ebola virus. 94. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Plasmodium falciparum. 95. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Marburg virus. 96. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Japanese encephalitis virus. 97. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for St. Louis encephalitis virus. 98. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for West Nile Virus. 99. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Yellow Fever virus. 100. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Bacillus anthracis. 101. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Botulinum toxin. 102. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Ricin. 103. The pharmaceutical composition of embodiment 55, wherein the coding nucleic acid sequence encodes a protein of interest for Shiga toxin and/or Shiga-like toxin. 104. The pharmaceutical composition of embodiments 43-103, wherein the polynucleotide comprises at least one modification. 105. The pharmaceutical composition of embodiment 104, wherein at least 20% of the bases are modified. 106. The pharmaceutical composition of embodiment 104, wherein at least 30% of the bases are modified. 107. The pharmaceutical composition of embodiment 104, wherein at least 40% of the bases are modified. 108. The pharmaceutical composition of embodiment 104, wherein at least 50% of the bases are modified. 109. The pharmaceutical composition of embodiment 104, wherein at least 60% of the bases are modified. 110. The pharmaceutical composition of embodiment 104, wherein at least 70% of the bases are modified. 111. The pharmaceutical composition of embodiment 104, wherein at least 80% of the bases are modified. 112. The pharmaceutical composition of embodiment 104, wherein at least 90% of the bases are modified. 113. The pharmaceutical composition of embodiment 104, wherein at least 100% of the bases are modified. 114. The pharmaceutical composition of embodiment 104, wherein a specific base comprises at least one modification. 115. The pharmaceutical composition of embodiment 114, wherein the base is adenine. 116. The pharmaceutical composition of embodiment 115, wherein at least 20% of the adenine bases are modified. 117. The pharmaceutical composition of embodiment 115, wherein at least 30% of the adenine bases are modified. 118. The pharmaceutical composition of embodiment 115, wherein at least 40% of the adenine bases are modified. 119. The pharmaceutical composition of embodiment 115, wherein at least 50% of the adenine bases are modified. 120. The pharmaceutical composition of embodiment 115, wherein at least 60% of the adenine bases are modified. 121. The pharmaceutical composition of embodiment 115, wherein at least 70% of the adenine bases are modified. 122. The pharmaceutical composition of embodiment 115, wherein at least 80% of the adenine bases are modified. 123. The pharmaceutical composition of embodiment 115, wherein at least 90% of the adenine bases are modified. 124. The pharmaceutical composition of embodiment 115, wherein at least 100% of the adenine bases are modified. 125. The pharmaceutical composition of embodiment 114, wherein the base is guanine. 126. The pharmaceutical composition of embodiment 125, wherein at least 20% of the guanine bases are modified. 127. The pharmaceutical composition of embodiment 125, wherein at least 30% of the guanine bases are modified. 128. The pharmaceutical composition of embodiment 125, wherein at least 40% of the guanine bases are modified. 129. The pharmaceutical composition of embodiment 125, wherein at least 50% of the guanine bases are modified. 130. The pharmaceutical composition of embodiment 125, wherein at least 60% of the guanine bases are modified. 131. The pharmaceutical composition of embodiment 125, wherein at least 70% of the guanine bases are modified. 132. The pharmaceutical composition of embodiment 125, wherein at least 80% of the guanine bases are modified. 133. The pharmaceutical composition of embodiment 125, wherein at least 90% of the guanine bases are modified. 134. The pharmaceutical composition of embodiment 125, wherein at least 100% of the guanine bases are modified. 135. The pharmaceutical composition of embodiment 114, wherein the base is cytosine. 136. The pharmaceutical composition of embodiment 135, wherein at least 20% of the cytosine bases are modified. 137. The pharmaceutical composition of embodiment 135, wherein at least 30% of the cytosine bases are modified. 138. The pharmaceutical composition of embodiment 135, wherein at least 40% of the cytosine bases are modified. 139. The pharmaceutical composition of embodiment 135, wherein at least 50% of the cytosine bases are modified. 140. The pharmaceutical composition of embodiment 135, wherein at least 60% of the cytosine bases are modified. 141. The pharmaceutical composition of embodiment 135, wherein at least 70% of the cytosine bases are modified. 142. The pharmaceutical composition of embodiment 135, wherein at least 80% of the cytosine bases are modified. 143. The pharmaceutical composition of embodiment 135, wherein at least 90% of the cytosine bases are modified. 144. The pharmaceutical composition of embodiment 135, wherein at least 100% of the cytosine bases are modified. 145. The pharmaceutical composition of embodiment 114, wherein the base is uracil. 146. The pharmaceutical composition of embodiment 145, wherein at least 20% of the uracil bases are modified. 147. The pharmaceutical composition of embodiment 145, wherein at least 30% of the uracil bases are modified. 148. The pharmaceutical composition of embodiment 145, wherein at least 40% of the uracil bases are modified. 149. The pharmaceutical composition of embodiment 145, wherein at least 50% of the uracil bases are modified. 150. The pharmaceutical composition of embodiment 145, wherein at least 60% of the uracil bases are modified. 151. The pharmaceutical composition of embodiment 145, wherein at least 70% of the uracil bases are modified. 152. The pharmaceutical composition of embodiment 145, wherein at least 80% of the uracil bases are modified. 153. The pharmaceutical composition of embodiment 145, wherein at least 90% of the uracil bases are modified. 154. The pharmaceutical composition of embodiment 145, wherein at least 100% of the uracil bases are modified. 155. The pharmaceutical composition of any of embodiments 104-154, wherein the at least one modification is pyridin-4-one ribonucleoside, 5-aza-uridine, 2-thio-5-aza-uridine, 2- thiouridine, 4-thio-pseudouridine, 2-thio-pseudouridine, 5-hydroxyuridine, 3-methyluridine, 5-carboxymethyl-uridine, 1-carboxymethyl-pseudouridine, 5-propynyl-uridine, 1-propynyl- pseudouridine, 5-taurinomethyluridine, 1-taurinomethyl-pseudouridine, 5-taurinomethyl-2- thio-uridine, 1-taurinomethyl-4-thio-uridine, 5-methyl-uridine, 1-methyl-pseudouridine, 4- thio-1-methyl-pseudouridine, 2-thio-1-methyl-pseudouridine, 1-methyl-1-deaza- pseudouridine, 2-thio-1-methyl-1-deaza-pseudouridine, dihydrouridine, dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2- methoxyuridine, 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, and 4-methoxy-2-thio- pseudouridine, 5-aza-cytidine, pseudoisocytidine, 3-methyl-cytidine, N4-acetylcytidine, 5- formylcytidine, N4-methylcytidine, 5-hydroxymethylcytidine, 1-methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo-pseudoisocytidine, 2-thio-cytidine, 2-thio-5-methyl-cytidine, 4-thio- pseudoisocytidine, 4-thio-1-methyl-pseudoisocytidine, 4-thio-1-methyl-1-deaza- pseudoisocytidine, 1-methyl-1-deaza-pseudoisocytidine, zebularine, 5-aza-zebularine, 5- methyl-zebularine, 5-aza-2-thio-zebularine, 2-thio-zebularine, 2-methoxy-cytidine, 2- methoxy-5-methyl-cytidine, 4-methoxy-pseudoisocytidine, and 4-methoxy-1-methyl- pseudoisocytidine, 2-aminopurine, 2, 6-diaminopurine, 7-deaza-adenine, 7-deaza-8-aza- adenine, 7-deaza-2-aminopurine, 7-deaza-8-aza-2-aminopurine, 7-deaza-2,6-diaminopurine, 7-deaza-8-aza-2,6-diaminopurine, 1-methyladenosine, N6-methyladenosine, N6- isopentenyladenosine, N6-(cis-hydroxyisopentenyl)adenosine, 2-methylthio-N6-(cis- hydroxyisopentenyl) adenosine, N6-glycinylcarbamoyladenosine, N6- threonylcarbamoyladenosine, 2-methylthio-N6-threonyl carbamoyladenosine, N6,N6- dimethyladenosine, 7-methyladenine, 2-methylthio-adenine, and 2-methoxy-adenine, inosine, 1-methyl-inosine, wyosine, wybutosine, 7-deaza-guanosine, 7-deaza-8-aza-guanosine, 6-thio- guanosine, 6-thio-7-deaza-guanosine, 6-thio-7-deaza-8-aza-guanosine, 7-methyl-guanosine, 6- thio-7-methyl-guanosine, 7-methylinosine, 6-methoxy-guanosine, 1-methylguanosine, N2- methylguanosine, N2,N2-dimethylguanosine, 8-oxo-guanosine, 7-methyl-8-oxo-guanosine, 1- methyl-6-thio-guanosine, N2-methyl-6-thio-guanosine, or N2,N2-dimethyl-6-thio-guanosine. 156. The pharmaceutical composition of any of embodiments 41-155, further comprises a cationic lipid that is not a lipid of any one of embodiments 1-40. 157. The pharmaceutical composition of any of embodiments 41-156, further comprising a neutral lipid. 158. The pharmaceutical composition of any of embodiments 41-157, further comprising an anionic lipid. 159. The pharmaceutical composition of any of embodiments 41-158, further comprises a helper lipid. 160. The pharmaceutical composition of any of embodiments 41-159, further comprises a stealth lipid. 161. The pharmaceutical composition of any of embodiments 41-160, wherein the weight ratio of the compound to the polynucleotide is between 100:1 to 1:1. 162. The pharmaceutical composition of any of embodiments 41-161, wherein the composition elicits an immune response in a subject. 163. A vaccine formulation comprising the pharmaceutical composition of any of embodiments 41-162. 164. A method of vaccinating a subject against an infectious agent comprising: (a) contacting a subject with the vaccine formulation of embodiment 163; and (b) eliciting an immune response. 165. The method of embodiment 164, wherein the infectious agent is Campylobacter jejuni, Clostridium difficile, Entamoeba histolytica, enterotoxin B, Norwalk virus or norovirus, Helicobacter pylori, rotavirus, candida yeast, coronavirus including SARS-CoV, SARS-CoV- 2 and MERS-CoV, Enterovirus 71, Epstein-Barr virus, Gram-Negative Bacteria including Bordetella, Gram-Positive Bacteria including Clostridium tetani, Francisella tularensis, Streptococcus bacteria and Staphylococcus bacteria, and Hepatitis, Human Cytomegalovirus, Human Immunodeficiency Virus, Human Papilloma Virus, Influenza, John Cunningham Virus, Mycobacterium, Poxviruses, Pseudomonas aeruginosa, Respiratory Syncytial Virus, Rubella virus, Varicella zoster virus, Chikungunya virus, Dengue virus, Rabies virus, Trypanosoma cruzi and/or Chagas disease, Ebola virus, Plasmodium falciparum, Marburg virus, Japanese encephalitis virus, St. Louis encephalitis virus, West Nile Virus, Yellow Fever virus, Bacillus anthracis, Botulinum toxin, Ricin, or Shiga toxin, and/or Shiga-like toxin. 166. The method of embodiment 164, wherein the contacting is enteral (into the intestine), gastroenteral, epidural (into the dura mater), oral (by way of the mouth), transdermal, intracerebral (into the cerebrum), intracerebroventricular (into the cerebral ventricles), epicutaneous (application onto the skin), intradermal (into the skin itself), subcutaneous (under the skin), nasal administration (through the nose), intravenous (into a vein), intravenous bolus, intravenous drip, intra-arterial (into an artery), intramuscular (into a muscle), intracardiac (into the heart), intraosseous infusion (into the bone marrow), intrathecal (into the spinal canal), intraparenchymal (into brain tissue), intraperitoneal (infusion or injection into the peritoneum), intravesical infusion, intravitreal (through the eye), intracavernous injection (into a pathologic cavity) intracavitary (into the base of the penis), intravaginal administration, intrauterine, extra- amniotic administration, transdermal (diffusion through the intact skin for systemic distribution), transmucosal (diffusion through a mucous membrane), transvaginal, insufflation (snorting), sublingual, sublabial, enema, eye drops (onto the conjunctiva), ear drops, auricular (in or by way of the ear), buccal (directed toward the cheek), conjunctival, cutaneous, dental (to a tooth or teeth), electro-osmosis, endocervical, endosinusial, endotracheal, extracorporeal, hemodialysis, infiltration, interstitial, intra-abdominal, intra-amniotic, intra-articular, intrabiliary, intrabronchial, intrabursal, intracartilaginous (within a cartilage), intracaudal (within the cauda equine), intracisternal (within the cisterna magna cerebellomedularis), intracorneal (within the cornea), dental intracoronal, intracoronary (within the coronary arteries), intracorporus cavernosum (within the dilatable spaces of the corporus cavernosa of the penis), intradiscal (within a disc), intraductal (within a duct of a gland), intraduodenal (within the duodenum), intradural (within or beneath the dura), intraepidermal (to the epidermis), intraesophageal (to the esophagus), intragastric (within the stomach), intragingival (within the gingivae), intraileal (within the distal portion of the small intestine), intralesional (within or introduced directly to a localized lesion), intraluminal (within a lumen of a tube), intralymphatic (within the lymph), intramedullary (within the marrow cavity of a bone), intrameningeal (within the meninges), intramyocardial (within the myocardium), intraocular (within the eye), intraovarian (within the ovary), intrapericardial (within the pericardium), intrapleural (within the pleura), intraprostatic (within the prostate gland), intrapulmonary (within the lungs or its bronchi), intrasinal (within the nasal or periorbital sinuses), intraspinal (within the vertebral column), intrasynovial (within the synovial cavity of a joint), intratendinous (within a tendon), intratesticular (within the testicle), intrathecal (within the cerebrospinal fluid at any level of the cerebrospinal axis), intrathoracic (within the thorax), intratubular (within the tubules of an organ), intratumor (within a tumor), intratympanic (within the aurus media), intravascular (within a vessel or vessels), intraventricular (within a ventricle), iontophoresis (by means of electric current where ions of soluble salts migrate into the tissues of the body), irrigation (to bathe or flush open wounds or body cavities), laryngeal (directly upon the larynx), nasogastric (through the nose and into the stomach), occlusive dressing technique (topical route administration which is then covered by a dressing which occludes the area), ophthalmic (to the external eye), oropharyngeal (directly to the mouth and pharynx), parenteral, percutaneous, periarticular, peridural, perineural, periodontal, rectal, respiratory (within the respiratory tract by inhaling orally or nasally for local or systemic effect), retrobulbar (behind the pons or behind the eyeball), soft tissue, subarachnoid, subconjunctival, submucosal, topical, transplacental (through or across the placenta), transtracheal (through the wall of the trachea), transtympanic (across or through the tympanic cavity), ureteral (to the ureter), urethral (to the urethra), vaginal, caudal block, diagnostic, nerve block, biliary perfusion, cardiac perfusion, photopheresis, or spinal. 167. A method of delivering a polynucleotide encoding at least one protein of interest to an immune cell of a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any one of embodiments 41-162. 168. The method of embodiment 167, wherein the immune cell is a T cell. 169. The method of embodiment 168, wherein the T cell is a CD8+ T cell. 170. The method of embodiment 168, wherein the T cell is a T regulatory cell. 171. The method of embodiment 168, wherein the T cell is CD4+ T cell. 172. The method of embodiment 167, wherein the immune cell is a macrophage, dendritic cell, or liver immune cell. Enumerated Embodiments, Section B [0978] The present disclosure include the enumerated embodiments 1-115 listed within Section B: 1. A compound of Formula IA: or a pharmaceutically acceptable salt or solvate thereof, wherein: A is selected from the group consisting of -N(R 1a )- and -C(R')-OC(=O)(R 8a )-; R 1a is -L 1 -R 1 ; L 1 is C 2 -C 6 alkylenyl or –(CH 2 ) 2-6 -OC(=O)-; R 1 is selected from the group consisting of -OH, R 2a , R 2b , and R 2c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 3a , R 3b , and R 3c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 4a , R 4b , and R 4c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 5a , R 5b , and R 5c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 6a , R 6b , and R 6c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or R 6a and R 6b taken together with the nitrogen atom to which they are attached form a 4-to 8-membered heterocyclo; and R 6c is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 7a , R 7b , and R 7c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or R 7a and R 7b taken together with the nitrogen atom to which they are attached form a 4-to 8-membered heterocyclo; and R 7c is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R' is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R8a is - L 2 -R 8 ; L 2 is C 2 -C 6 alkylenyl; R 8 is selected from the group consisting of -NR 9a R 9b , R 9a and R 9b are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or R 9a and R 9b taken together with the nitrogen atom to which they are attached form a 4-to 8-membered heterocyclo; Q 1 is C 1 -C 20 alkylenyl; W 1 is selected from the group consisting of -C(=O)O-, -OC(=O)-, -C(=O)N(R 12a )- , -N(R 12a )C(=O)-, -OC(=O)N(R 12a )-, - N(R 12a )C(=O)O-, and -OC(=O)O-; R 12a is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; X 1 is optionally substituted C 1 -C 15 alkylenyl; or X 1 is a bond; Y 1 is selected from the group consisting of -(CH 2 ) m -, -O-, -S-, and -S-S-; m is 0, 1, 2, 3, 4, 5, or 6; Z 1 is selected from the group consisting of optionally substituted C 4 -C 12 cycloalkylenyl, R 10 is selected from the group consisting of hydrogen, C 1 -C 20 alkyl, and C 2 -C 20 alkenyl; Q 2 is C 1 -C 20 alkylenyl; W 2 is selected from the group consisting of -C(=O)O-, -C(=O)N(R 12b )-, -OC(=O)N(R 12b )- , and -OC(=O)O-; R 12b is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; X 2 is optionally substituted C 1 -C 15 alkylenyl; or X 2 is a bond; Y 2 is selected from the group consisting of -(CH 2 ) n -, -O-, -S-, and -S-S-; n is 0, 1, 2, 3, 4, 5, or 6; Z 2 is selected from the group consisting of -(CH 2 ) p -, optionally substituted C 4 -C 12 cycloalkylenyl, p is 0 or 1; and R 11 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, and C 2 -C 10 alkenyl; wherein one or more methylene linkages of X 1 , X 2 , Y 1 , Y 2 , Z 1 , Z 2 , R 10 , and R 11 , are optionally and independently replaced with a group selected from -O-, -CH=CH-, -S- and C 3 -C 6 cycloalkylenyl. 2. A compound of Formula IB: or a pharmaceutically acceptable salt or solvate thereof, wherein: A is selected from the group consisting of -N(R 1a )- and -C(R')-OC(=O)(R 8a )-; R 1a is -L 1 -R 1 ; L 1 is C 2 -C 6 alkylenyl or –(CH 2 ) 2-6 -OC(=O)-; R 1 is selected from the group consisting of -OH, R 2a , R 2b , and R 2c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 3a , R 3b , and R 3c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 4a , R 4b , and R 4c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 5a , R 5b , and R 5c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 6a , R 6b , and R 6c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or R 6a and R 6b taken together with the nitrogen atom to which they are attached form a 4-to 8-membered heterocyclo; and R 6c is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 7a , R 7b , and R 7c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or R 7a and R 7b taken together with the nitrogen atom to which they are attached form a 4-to 8-membered heterocyclo; and R 7c is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R' is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 8a is - L 2 -R 8 ; L 2 is C 2 -C 6 alkylenyl; R 8 is selected from the group consisting of -NR 9a R 9b , R 9a and R 9b are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or R 9a and R 9b taken together with the nitrogen atom to which they are attached form a 4-to 8-membered heterocyclo; Q 1 is C 1 -C 20 alkylenyl; W 1 is selected from the group consisting of -C(=O)O-, -OC(=O)-, -C(=O)N(R 12a )- , -N(R 12a )C(=O)-, -OC(=O)N(R 12a )-, - N(R 12a )C(=O)O-, and -OC(=O)O-; R 12a is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; X 1 is optionally substituted C 1 -C 15 alkylenyl; or X 1 is a bond; Y 1 is selected from the group consisting of -(CH 2 ) m -, -O-, -S-, and -S-S-; m is 0, 1, 2, 3, 4, 5, or 6; Z 1 is selected from the group consisting of optionally substituted C 5 -C 12 bridged cycloalkylenyl, R 10 is selected from the group consisting of hydrogen, C 1 -C 20 alkyl, and C 2 -C 20 alkenyl; Q 2 is C 1 -C 20 alkylenyl; W 2 is selected from the group consisting of -C(=O)O-, -C(=O)N(R 12b )-, -OC(=O)N(R 12b )- , and -OC(=O)O-; R 12b is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; X 2 is optionally substituted C 1 -C 15 alkylenyl; or X 2 is a bond; Y 2 is selected from the group consisting of -(CH 2 ) n -, -O-, -S-, and -S-S-; n is 0, 1, 2, 3, 4, 5, or 6; Z 2 is selected from the group consisting of -(CH 2 ) p -, optionally substituted C 4 -C 12 cycloalkylenyl, p is 0 or 1; and R 11 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, and C 2 -C 10 alkenyl; wherein one or more methylene linkages of X 1 , X 2 , Y 1 , Y 2 , Z 1 , Z 2 , R 10 , and R 11 , are optionally and independently replaced with a group selected from -O-, -CH=CH-, -S- and C 3 -C 6 cycloalkylenyl. 3. A compound of Formula IC: or a pharmaceutically acceptable salt or solvate thereof, wherein: A is selected from the group consisting of -N(R 1a )- and -C(R')-OC(=O)(R 8a )-; R 1a is -L 1 -R 1 ; L 1 is C 2 -C 6 alkylenyl or –(CH 2 ) 2-6 -OC(=O)-; R 1 is selected from the group consisting of -OH, R 2a , R 2b , and R 2c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 3a , R 3b , and R 3c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 4a , R 4b , and R 4c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 5a , R 5b , and R 5c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 6a , R 6b , and R 6c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or R 6a and R 6b taken together with the nitrogen atom to which they are attached form a 4-to 8-membered heterocyclo; and R 6c is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 7a , R 7b , and R 7c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or R 7a and R 7b taken together with the nitrogen atom to which they are attached form a 4-to 8-membered heterocyclo; and R 7c is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R' is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 8a is - L 2 -R 8 ; L 2 is C 2 -C 6 alkylenyl; R 8 is selected from the group consisting of -NR 9a R 9b , R 9a and R 9b are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or R 9a and R 9b taken together with the nitrogen atom to which they are attached form a 4-to 8-membered heterocyclo; Q 1 is C 1 -C 20 alkylenyl; W 1 is selected from the group consisting of -C(=O)O-, -OC(=O)-, -C(=O)N(R 12a )- , -N(R 12a )C(=O)-, -OC(=O)N(R 12a )-, - N(R 12a )C(=O)O-, and -OC(=O)O-; R 12a is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; X 1 is optionally substituted branched C 1 -C 15 alkylenyl; or X 1 is a bond; Y 1 is selected from the group consisting of -(CH 2 ) m -, -O-, -S-, and -S-S-; m is 0, 1, 2, 3, 4, 5, or 6; Z 1 is selected from the group consisting of optionally substituted C 4 -C 12 cycloalkylenyl, R 10 is selected from the group consisting of hydrogen, C 1 -C 20 alkyl, and C 2 -C 20 alkenyl; Q 2 is C 1 -C 20 alkylenyl; W 2 is selected from the group consisting of -C(=O)O-, -C(=O)N(R 12b )-, -OC(=O)N(R 12b )- , and -OC(=O)O-; R 12b is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; X 2 is optionally substituted C 1 -C 15 alkylenyl; or Y 2 is selected from the group consisting of -(CH 2 ) n -, -O-, -S-, and -S-S-; n is 0, 1, 2, 3, 4, 5, or 6; Z 2 is of -(CH 2 ) p -; p is 0 or 1; and R 11 is C 1 -C 20 branched alkyl; wherein one or more methylene linkages of X 1 , X 2 , Y 1 , Y 2 , Z 1 , Z 2 , R 10 , and R 11 , are optionally and independently replaced with a group selected from -O-, -CH=CH-, -S- and C 3 -C 6 cycloalkylenyl. 4. A compound of Formula ID: or a pharmaceutically acceptable salt or solvate thereof, wherein: A is selected from the group consisting of -N(R 1a )- and -C(R')-OC(=O)(R 8a )-; R 1a is -L 1 -R 1 ; L 1 is C 2 -C 6 alkylenyl or –(CH 2 ) 2-6 -OC(=O)-; R 1 is selected from the group consisting of -OH, R 2a , R 2b , and R 2c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 3a , R 3b , and R 3c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 4a , R 4b , and R 4c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 5a , R 5b , and R 5c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 6a , R 6b , and R 6c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or R 6a and R 6b taken together with the nitrogen atom to which they are attached form a 4-to 8-membered heterocyclo; and R 6c is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 7a , R 7b , and R 7c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or R 7a and R 7b taken together with the nitrogen atom to which they are attached form a 4-to 8-membered heterocyclo; and R 7c is selected from the group consisting of hydrogen a nd C 1-C6 alkyl; R' is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 8a is - L 2 -R 8 ; L 2 is C 2 -C 6 alkylenyl; R 8 is selected from the group consisting of -NR 9a R 9b , R 9a and R 9b are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or R 9a and R 9b taken together with the nitrogen atom to which they are attached form a 4-to 8-membered heterocyclo; Q 1 is C 1 -C 20 alkylenyl; W 1 is selected from the group consisting of -C(=O)O-, -OC(=O)-, -C(=O)N(R 12a )- , -N(R 12a )C(=O)-, -OC(=O)N(R 12a )-, - N(R 12a )C(=O)O-, and -OC(=O)O-; R 12a is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; X 1 is optionally substituted branched C 1 -C 15 alkylenyl; or X 1 is a bond; Y 1 is selected from the group consisting of -(CH 2 ) m -, -O-, -S-, and -S-S-; m is 0, 1, 2, 3, 4, 5, or 6; Z 1 is optionally substituted C 5 -C 12 bridged cycloalkylenyl; R 10 is selected from the group consisting of hydrogen, C 1 -C 20 alkyl, and C 2 -C 20 alkenyl; Q 2 is C 1 -C 20 alkylenyl; W 2 is selected from the group consisting of -C(=O)O-, -C(=O)N(R 12b )-, -OC(=O)N(R 12b )- , and -OC(=O)O-; R 12b is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; X 2 is optionally substituted C 1 -C 15 alkylenyl; or Y 2 is -(CH 2 ) n -; n is 0, 1, 2, 3, 4, 5, or 6; Z 2 is of -(CH 2 ) p -; p is 0 or 1; and R 11 is C 1 -C 20 branched alkyl. 5. A compound of Formula I: or a pharmaceutically acceptable salt or solvate thereof, wherein: A is selected from the group consisting of -N(R 1a )- and -C(R')-OC(=O)(R 8a )-; R 1a is -L 1 -R 1 ; L 1 is C 2 -C 6 alkylenyl; R 1 is selected from the group consisting of -OH, R 2a , R 2b , and R 2c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 3a , R 3b , and R 3c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 4a , R 4b , and R 4c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 5a , R 5b , and R 5c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 6a , R 6b , and R 6c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or R 6a and R 6b taken together with the nitrogen atom to which they are attached form a 4-to 8-membered heterocyclo; and R 6c is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 7a , R 7b , and R 7c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or R 7a and R 7b taken together with the nitrogen atom to which they are attached form a 4-to 8-membered heterocyclo; and R 7c is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R' is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 8a is - L 2 -R 8 ; L 2 is C 2 -C 6 alkylenyl; R 8 is -NR 9a R 9b ; R 9a and R 9b are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or R 9a and R 9b taken together with the nitrogen atom to which they are attached form a 4-to 8-membered heterocyclo; Q 1 is C 1 -C 20 alkylenyl; W 1 is selected from the group consisting of -C(=O)O-, -OC(=O)-, -C(=O)N(R 12a )- , -N(R 12a )C(=O)-, -OC(=O)N(R 12a )-, - N(R 12a )C(=O)O-, and -OC(=O)O-; R 12a is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; X 1 is C 1 -C 15 alkylenyl; or X 1 is a bond; Y 1 is selected from the group consisting of -(CH 2 ) m -, -O-, -S-, and -S-S-; m is 0, 1, 2, 3, 4, 5, or 6; Z 1 is selected from the group consisting of C 4 -C 12 cycloalkylenyl, R 10 is selected from the group consisting of hydrogen, C 1 -C 20 alkyl, and C 2 -C 20 alkenyl; Q 2 is C 1 -C 20 alkylenyl; W 2 is selected from the group consisting of -C(=O)O-, -C(=O)N(R 12b )-, -OC(=O)N(R 12b )- , and -OC(=O)O-; R 12b is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; X 2 is C 1 -C 15 alkylenyl; or X 2 is a bond; Y 2 is selected from the group consisting of -(CH 2 ) n -, -O-, -S-, and -S-S-; n is 0, 1, 2, 3, 4, 5, or 6; Z 2 is selected from the group consisting of -(CH 2 ) p -, C 4 -C 12 cycloalkylenyl, p is 0 or 1; and R 11 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, and C 2 -C 10 alkenyl. 6. The compound of any of embodiments 1-5 of Formula II: or a pharmaceutically acceptable salt or solvate thereof. 7. The compound of any of embodiments 1-5 of Formula III: or a pharmaceutically acceptable salt or solvate thereof. 8. The compound of any of embodiments 1-5 of Formula IV: or a pharmaceutically acceptable salt or solvate thereof, wherein R', R 9a , R 9b , R 10 , R 11 , L 2 , Q 1 , Q 2 , W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , Z 1 , and Z 2 are as defined herein in Formula IA, Formula IB, Formula IC, Formula ID, Formula I, or below, with the proviso that -Q 1 - W 1 -X 1 -Y 1 -Z 1 -R 10 is not the same as -Q 2 -W 2 -X 2 -Y 2 -Z 2 -R 11 , i.e., the carbon atom bearing R' is an asymmetrical carbon atom. 9. The compound of any of embodiments 1-5 of Formula V: or a pharmaceutically acceptable salt or solvate thereof, wherein R', R 9a , R 9b , R 10 , R 11 , L 2 , Q 1 , Q 2 , W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , Z 1 , and Z 2 are as defined herein in Formula IA, Formula IB, Formula IC, Formula ID, Formula I, or below, with the proviso that -Q 1 - W 1 -X 1 -Y 1 -Z 1 -R 10 is not the same as -Q 2 -W 2 -X 2 -Y 2 -Z 2 -R 11 , i.e., the carbon atom bearing R' is an asymmetrical carbon atom. 10. The compound of any of embodiments 1-9, wherein W 1 is -C(=O)O- or -OC(=O)-. 11. The compound of any of embodiments 1-10, wherein W 2 is -C(=O)O- or -OC(=O)-. 12. The compound of any of embodiments 1-5 of Formula VI, VI’, VI’’, or VI’’’: or a pharmaceutically acceptable salt or solvate thereof. 13. The compound of any of embodiments 1-5 of Formula VII, VII’, VII’’, or VII’’’: or a pharmaceutically acceptable salt or solvate thereof. 14. The compound of any of embodiments 1-13, wherein Q 1 is optionally substituted straight chain C 1 -C 10 alkylenyl, and Q 2 is optionally substituted straight chain C 1 -C 10 alkylenyl. 15. The compound of embodiment 14, wherein Q 1 is optionally substituted straight chain C 3 -C 7 alkylenyl, and Q 2 is optionally substituted straight chain C 3 -C 7 alkylenyl. 16. The compound of embodiment 15, wherein Q 1 is selected from the group consisting of -CH 2 CH 2 CH 2 -, -CH 2 (CH 2 ) 2 CH 2 -, -CH 2 (CH 2 ) 3 CH 2 -, -CH 2 (CH 2 ) 4 CH 2 -, and -CH 2 (CH 2 ) 5 CH 2 -, and Q 2 is selected from the group consisting of -CH 2 CH 2 CH 2 - , -CH 2 (CH 2 ) 2 CH 2 -, -CH 2 (CH 2 ) 3 CH 2 -, -CH 2 (CH 2 ) 4 CH 2 -, and -CH 2 (CH 2 ) 5 CH 2 -. 17. The compound of any of embodiments 1-5 of Formula VIII, VIII’, VIII’’, or VIII’’: or a pharmaceutically acceptable salt or solvate thereof, wherein q 1 is 0, 1, 2, or 3; q 2 is 0, 1, 2, or 3. 18. The compound of any of embodiments 1-5 of Formula IX, IX’, IX’’, or IX’’: or a pharmaceutically acceptable salt or solvate thereof, wherein q 1 is 0, 1, 2, or 3; q 2 is 0, 1, 2, or 3. 19. The compound of any of embodiments 1-5 of Formula X, X’, X’’, or X’’: or a pharmaceutically acceptable salt or solvate thereof, wherein q 1 is 0, 1, 2, or 3; q 2 is 0, 1, 2, or 3. 20. The compound of any of embodiments 1-5 of Formula XI, XI’, XI’’, or XI’’’: or a pharmaceutically acceptable salt or solvate thereof wherein q 1 is 0, 1, 2, or 3; q 2 is 0, 1, 2, or 3; r 2 is 0, 1, or 2; s 2 is 0, 1, 2, 3, 4, 5, 6. 21. The compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 is a bond. 22. The compound of any of embodiments 1-21, wherein X 2 is optionally substituted C 1 - C 15 branched alkylenyl. 23. The compound of any of embodiments 1-9, -Q 1 -W 1 -X 1 -Y 1 -Z 1 -R 10 is selected from the group consisting of:
24. The compound of any of embodiments 1-9, -Q 2 -W 2 -X 2 -Y 2 -Z 2 -R 11 is selected from the group consisting of:
25. The compound of any of embodiments 1-5 of Formula XII, XII’, XII’’, or XII’’’: or a pharmaceutically acceptable salt or solvate thereof, wherein q 1 is 0, 1, 2, or 3; q 2 is 0, 1, 2, or 3; r 2 is 0, 1, or 2; s 2 is 0, 1, 2, 3, 4, 5, 6. 26. The compound of any of embodiments 1-5, of Formula XIII, XIII’, XIII’’, or XIII’’’: or a pharmaceutically acceptable salt or solvate thereof, wherein q 1 is 0, 1, 2, or 3; q 2 is 0, 1, 2, or 3; r 2 is 0, 1, or 2; s 2 is 0, 1, 2, 3, 4, 5, 6. 27. The compound of any of embodiments 1-5, of Formula XIV, XIV’, XIV’’, or XIV’’’: or a pharmaceutically acceptable salt or solvate thereof, wherein R 11’ is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, and C 2 -C 10 alkenyl; q 1 is 0, 1, 2, or 3; q 2 is 0, 1, 2, or 3; r 2 is 0, 1, or 2; s 2 is 0, 1, 2, 3, 4, 5, 6. 28. The compound of any of embodiments 1-5, of Formula XV, XV’, XV’’, or XV’’’: or a pharmaceutically acceptable salt or solvate thereof, wherein R 11’ is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, and C 2 -C 10 alkenyl; q 1 is 0, 1, 2, or 3; q 2 is 0, 1, 2, or 3; r 2 is 0, 1, or 2; s 2 is 0, 1, 2, 3, 4, 5, 6. 29. The compound of any of embodiments 1-5, of Formula XVI, XVI’, XVI’’, or XVI’’’: or a pharmaceutically acceptable salt or solvate thereof, wherein R 11’ is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, and C 2 -C 10 alkenyl; q 1 is 0, 1, 2, or 3; q 2 is 0, 1, 2, or 3; r 2 is 0, 1, or 2; s 2 is 0, 1, 2, 3, 4, 5, 6. 30. The compound of any of embodiments 1-29, wherein Z 1 is optionally substituted C 5 - C 12 bridged cycloalkylenyl. 31. The compound of embodiment 30, wherien Z 1 is a optionally substituted C 5 -C 10 bridged cycloalkylenyl. selected from the group consisting of adamantyl, cubanyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[1.1.1]pentyl, bicyclo[3.2.1]octyl, and bicyclo[3.1.1]heptyl. 32. The compound of embodiment 30, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 1 is selected from the group consisting of: 33. The compound of embodiment 32, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 1 is selected from the group consisting of: 34. The compound of embodiment 32, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 1 is selected from the group consisting of: 35. The compound of any of embodiments 1-11, of Formula XVII: or a pharmaceutically acceptable salt or solvate thereof, wherein q 1 is 0, 1, 2, or 3; q 2 is 0, 1, 2, or 3. 36. The compound of any of embodiments 1-11, of Formula XVIII or XVIII’: or a pharmaceutically acceptable salt or solvate thereof, wherein q 1 is 0, 1, 2, or 3; q 2 is 0, 1, 2, or 3. 37. The compound of any of embodiments 1-11, of Formula XIX: or a pharmaceutically acceptable salt or solvate thereof, wherein q 1 is 0, 1, 2, or 3; q 2 is 0, 1, 2, or 3. 38. The compound of any of embodiments 1-11, of Formula XX: or a pharmaceutically acceptable salt or solvate thereof, wherein q 1 is 0, 1, 2, or 3; q 2 is 0, 1, 2, or 3. q 2 is 0, 1, 2, or 3. 39. The compound of any of embodiments 1-11, of Formula XXI: or a pharmaceutically acceptable salt or solvate thereof, wherein q 1 is 0, 1, 2, or 3; q 2 is 0, 1, 2, or 3. 40. The compound of any of embodiments 1-39, wherein Z 2 is optionally substituted C 5 - C 12 bridged cycloalkylenyl. 41. The compound of embodiment 40, wherien Z 2 is a optionally substituted C 5 -C 10 bridged cycloalkylenyl. selected from the group consisting of adamantyl, cubanyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[1.1.1]pentyl, bicyclo[3.2.1]octyl, and bicyclo[3.1.1]heptyl. 42. The compound of embodiment 41, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 2 is selected from the group consisting of: 43. The compound of embodiment 42, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 2 is selected from the group consisting of: 44. The compound of any of embodiments 1-39, wherein Z 2 is -CH 2 -. 45. The compound of any of embodiments 1-44, or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is selected from the group consisting of -CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, and -CH 2 CH 2 CH 2 CH 2 -. 46. The compound of embodiment 45, wherein L is -CH 2 CH 2 -. 47. The compound of embodiment 45, wherein L is -CH2CH2CH2-. 48. The compound of any one of embodiments 1-47, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl. 49. The compound of embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b are methyl. 50. The compound of any one of embodiments 1-49, or a pharmaceutically acceptable salt or solvate thereof, wherein R' is hydrogen. 51. The compound of any one of embodiments 1-50, or a pharmaceutically acceptable salt or solvate thereof, wherein Y 1 is -(CH 2 ) m -; and m is 1. 52. The compound of any one of embodiments 1-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R 10 is hydrogen. 53. The compound of any one of embodiments 1-52, or a pharmaceutically acceptable salt or solvate thereof, wherein Y 2 is selected from the group consisting of -(CH 2 ) m - and -S-. 54. The compound of any one of embodiments 1-53, or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is C 1 -C 10 alkyl. 55. The compound of any one of embodiments 1-54, or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 is C 2 -C 10 alkenyl. 56. A compound selected from any one of more of the compounds of Table 1, or a pharmaceutically acceptable salt or solvate thereof. 57. A pharmaceutical composition comprising: (a) a polynucleotide encoding at least one protein of interest; and (b) a delivery vehicle comprising one or more compounds of any one of embodiments 1-56. 58. The pharmaceutical composition of embodiment 57, wherein the polynucleotides are DNA. 59. The pharmaceutical composition of embodiment 57, wherein the polynucleotides are RNA. 60. The pharmaceutical composition of embodiment 59, wherein the RNA are short interfering RNA (siRNA). 61. The pharmaceutical composition of embodiment 60, wherein the siRNA inhibits or suppresses the expression of a target of interest in a cell. 62. The pharmaceutical composition of any one of embodiments 58-61, wherein the polynucleotide comprises at least one modification. 63. The pharmaceutical composition of any of embodiments 57-62, further comprising an additional cationic lipid. 64. The pharmaceutical composition of any of embodiments 57-63, further comprising a neutral lipid. 65. The pharmaceutical composition of any of embodiments 57-64, further comprising an anionic lipid. 66. The pharmaceutical composition of any of embodiments 57-65, further comprising a helper lipid. 67. The pharmaceutical composition of any of embodiments 57-66, further comprising a stealth lipid. 68. The pharmaceutical composition of any of embodiments 57-67, wherein the weight ratio of the lipids and the polynucleotide is from about 100:1 to about 1:1. 69. A vaccine formulation comprising the pharmaceutical composition of any of embodiments 57-68. 70. A vaccine preparation comprising the pharmaceutical composition of any of embodiments 57-69. 71. A method of vaccinating a subject against an infectious agent comprising: a) contacting a subject with the vaccine formulation of embodiment 69 or the vaccine preparation of embodiment 70, and b) eliciting an immune response. 72. A method of delivering a polynucleotide encoding at least one protein of interest to an immune cell of a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any one of embodiments 57-68. 73. The method of embodiment 72, wherein the immune cell is a T cell. 74. The method of embodiment 73, wherein the T cell is a CD8+ T cell. 75. The method of embodiment 74, wherein the T cell is a T regulatory cell. 76. The method of embodiment 75, wherein the T cell is a CD4+ T cell. 77. The method of embodiment 76, wherein the immune cell is a macrophage, dendritic cell, or liver immune cell. 78. A lipid nanoparticle (LNP) comprising a compound of any one of embodiments 1- 56, or a pharmaceutically acceptable salt thereof. 79. The LNP of embodiment 78, further comprising: (a) a PEG-lipid (b) a structural lipid; and (c) a non-ionizable lipid and/or a zwitterionic lipid. 80. The LNP of embodiment 79, wherein the ionizable lipid comprises an ionizable amino lipid. 81. The LNP of embodiment 79 or 80, wherein the PEG-lipid is selected from the group consisting of PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG-DMPE, PEG-DPPC, and PEG-DSPE. 82. The LNP of any one of embodiments 79-81, wherein the structural lipid is selected from the group consisting of cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, an alpha- tocopherol. 83. The LNP of any one of embodiments 79-82, wherein the non-ionizable lipid is a phospholipid selected from the group consisting of 1,2-distearoyl-sn-glycero-3- phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero- phosphocholine (DMPC), 1.2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2- dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-diundecanoyl-sn-glycero- phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocho line (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1- oleoyl-2-cholesterylhemisuc cinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1- hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero- 3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2- didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-diphytanoylsn-glycero-3- phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3- phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2- dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3- phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), sodium (S)-2-ammonio-3-((((R)-2-(oleoyloxy)-3- (stearoyloxy)propoxy)oxidophosphoryl)oxy)propanoate (L-α-phosphatidylserine; Brain PS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dioleoyl- phosphatidylethanolamine4-(N-maleimidomethyl)-cyclohexane-1- carboxylate (DOPE-mal), dioleoylphosphatidylglycerol (DOPG), 1,2-dioleoyl-sn-glycero-3- (phospho-L-serine) (DOPS), acell-fusogenicphospholipid (DPhPE), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylcholine (DSPC), distearoyl-phosphatidyl-ethanolamine (DSPE), distearoyl phosphoethanolamineimidazole (DSPEI), 1,2-diundecanoyl-sn-glycero- phosphocholine (DUPC), egg phosphatidylcholine (EPC), 1,2-dioleoyl-sn-glycero-3- phosphate (18:1 PA; DOPA), ammonium bis((S)-2-hydroxy-3-(oleoyloxy)propyl) phosphate (18:1 DMP; LBPA), 1,2-dioleoyl-sn-glycero-3-phospho-(1’-myo-inositol) (DOPI; 18:1 PI), 1,2-distearoyl-sn-glycero-3-phospho-L-serine (18:0 PS), 1,2- dilinoleoyl-sn-glycero-3-phospho-L-serine (18:2 PS), 1-palmitoyl-2-oleoyl-sn- glycero-3-phospho-L-serine (16:0-18:1 PS; POPS), 1-stearoyl-2-oleoyl-sn-glycero-3- phospho-L-serine (18:0-18:1 PS), 1-stearoyl-2-linoleoyl-sn-glycero-3-phospho-L- serine (18:0-18:2 PS), 1-oleoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:1 Lyso PS), 1-stearoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:0 Lyso PS), and sphingomyelin. 84. The LNP of any one of embodiments 79-83, further comprising a targeting moiety. 85. The LNP of embodiment 84, wherein the targeting moiety is an antibody or a fragment thereof. 86. The LNP of any one of embodiments 79-85, further comprising an active agent. 87. The LNP of embodiment 86, wherein the active agent is a nucleic acid. 88. The LNP of embodiment 87, wherein the nucleic acid is a ribonucleic acid. 89. The LNP of embodiment 88, wherein the ribonucleic acid is at least one ribonucleic acid selected from the group consisting of a small interfering RNA (siRNA), an asymmetrical interfering RNA (aiRNA), a microRNA (miRNA), a Dicer-substrate RNA (dsRNA), a small hairpin RNA (shRNA), a messenger RNA (mRNA), and a long non-coding RNA (lncRNA). 90. The LNP of embodiment 87, wherein the nucleic acid is a messenger RNA (mRNA) or a circular RNA. 91. The LNP of embodiment 90, wherein the mRNA includes an open reading frame encoding a cancer antigen. 92. The LNP of embodiment 91, wherein the mRNA includes an open reading frame encoding an immune checkpoint modulator. 93. The LNP of any one of embodiments 90-92, wherein the mRNA includes at least one motif selected from the group consisting of a stem loop, a chain terminating nucleoside, a polyA sequence, a polyadenylation signal, and a 5' cap structure. 94. The LNP of embodiment 87, wherein, wherein the nucleic acid is a polynucleotide that encodes a protein selected from SEQ ID NOs: 1-54. 95. The LNP of embodiment 87, wherein the nucleic acid is suitable for a genome editing technique. 96. The LNP of embodiment 95, wherein the genome editing technique is clustered regularly interspaced short palindromic repeats (CRISPR) or transcription activator- like effector nuclease (TALEN). 97. The LNP of embodiment 87, wherein the nucleic acid is at least one nucleic acid suitable for a genome editing technique selected from the group consisting of a CRISPR RNA (crRNA), a trans-activating crRNA (tracrRNA), a single guide RNA (sgRNA), and a DNA repair template. 98. The LNP of embodiment 90, wherein the mRNA is at least 30 nucleotides in length. 99. The LNP of embodiment 90, wherein the mRNA is at least 300 nucleotides in length. 100. A pharmaceutical composition comprising a LNP of any one of embodiments 78-99, and a pharmaceutically acceptable carrier. 101. The pharmaceutical composition of embodiment 100, formulated for intravenous or intramuscular administration. 102. The pharmaceutical composition of embodiment 101, which is formulated for intravenous administration. 103. A method for delivering a nucleic acid to a cell comprising contacting the cell with a LNP of any one of embodiments 78-99 or a pharmaceutical composition of any one of embodiments 100-102. 104. A method for treating a disease characterized by a deficieincy of a functional protein, the method comprising administering to a subject having the disease, a LNP formulation comprising a LNP of any one of embodiments 78-99, wherein the mRNA encodes the functional protein or a protein having the same biological activity as the functional protein. 105. A method for treating a disease characterized by overexpression of a polypeptide, comprising administering to a subject having the disease a LNP formulation comprising a LNP of any one of embodiments 78-99 and a siRNA, wherein the siRNA targets expression of the overexpressed polypeptide 106. A method of delivering a polynucleotide encoding at least one protein of interest to a cell of interest of a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any one of embodiments 57-68, 100-102 or a LNP of any one of embodiments 78-99. 107. The mehod of embodiment 106, wherein the cell is selected from the group consisting of hepatocyte, epithelial cell, hematopoietic cell, epithelial cell, endothelial cell, lung cell, bone cell, stem cell, mesenchymal cell, neural cell, cardiac cell, adipocyte, vascular smooth muscle cell, cardiomyocyte, skeletal muscle cell, beta cell, pituitary cell, synovial lining cell, ovarian cell, testicular cell, fibroblast, B cell, T cell, reticulocyte, leukocyte, granulocyte, and tumor cell. 108. The method of embodiment 106, wherein the cell is an immune cell. 109. The method of embodiment 108, wherein the immune cell is a T cell. 110. The method of embodiment 109, wherein the T cell is a CD8+ T cell. 111. The method of embodiment 109, wherein the T cell is a T regulatory cell. 112. The method of embodiment 109, wherein the T cell is CD4+ T cell. 113. The method of embodiment 108, wherein the immune cell is a B cell. 114. The method of embodiment 109, wherein the immune cell is a macrophage, dendritic cell, or liver immune cell. 115. The method of embodiment 106, wherein the cell is a hematopoietic cell.
X. DEFINITIONS [0979] The term "compound" or "structure," as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. [0980] The compounds or structures described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms. [0981] Compounds or structures of the present disclosure also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Examples prototropic tautomers include ketone – enol pairs, amide – imidic acid pairs, lactam – lactim pairs, amide – imidic acid pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. [0982] Compounds or structures of the present disclosure also include all of the isotopes of the atoms occurring in the intermediate or final compounds. "Isotopes" refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium. [0983] The compounds or structures and salts of the present disclosure can be prepared in combination with solvent or water molecules to form solvates and hydrates by routine methods. [0984] The term "alkyl" refers to the radical of saturated aliphatic groups, including straight- chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl- substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. [0985] In some embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C 1 -C 30 for straight chains, C 3 -C 30 for branched chains), 20 or fewer, 12 or fewer, or 7 or fewer. Likewise, in some embodiments cycloalkyls have from 3-10 carbon atoms in their ring structure, e.g., have 5, 6 or 7 carbons in the ring structure. The term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents include, but are not limited to, halogen, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, a hosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. [0986] Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to ten carbons, or from one to six carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths. In some embodiments, alkyl groups are lower alkyls. In some embodiments, a substituent designated herein as alkyl is a lower alkyl. [0987] The term "alkylenyl" as used herein refers to a divalent radical of a straight-chain or branched-chain alkyl group. In one embodiment, the alkylenyl is a divalent form of a C 1-12 alkyl, i.e., a C 1 -C 12 alkylenyl. In one embodiment, the alkylenyl is a divalent form of a C 2-6 alkyl, i.e., a C 1 -C 10 alkylenyl. In one embodiment, the alkylenyl is a divalent form of a C 2-14 alkyl, i.e., a C 1 -C 8 alkylenyl. In one embodiment, the alkylenyl is a divalent form of an unsubstituted C 1-6 alkyl, i.e., a C 1 -C 6 alkylenyl. In another embodiment, the alkylenyl is a divalent form of an unsubstituted C 1-4 alkyl, i.e., a C 1 -C 4 alkylenyl. Non-limiting exemplary alkylenyl groups include -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, - CH 2 (CH 2 ) 2 CH 2 -, -CH(CH 2 ) 3 CH 2 -, and -CH 2 (CH 2 ) 4 CH 2 -. [0988] The term "cycloalkylenyl" as used herein refers to a divalent radical of a cycloalkyl group. In one embodiment, the cycloalkylenyl is a divalent form of a C 3-8 cycloalkyl, i.e., a C 3 -C 8 cycloalkylenyl. Non-limiting exemplary cycloalkylenyl groups include: . In some embodiments, a cycloalkylenyl is a bicyclic group. In some embodiments, a cycloalkylenyl is a tricyclic group. In some embodiments, a cycloalkylenyl is a polycyclic group. In some embodiments, a cycloalkylenyl includes a group comprising two or more cycloalkyl groups that are fused or bridged together. Non-limiting exemplary cycloalkylenyl groups include adamantyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[1.1.1]pentyl, and bicyclo[3.2.1]octyl. [0989] It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include halogen, hydroxy, nitro, thiols, amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF 3 , -CN and the like. Cycloalkyls can be substituted in the same manner. [0990] The term "heteroalkyl", as used herein, refers to straight or branched chain, or cyclic carbon-containing radicals, or combinations thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, Se, B, and S, wherein the phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups. [0991] The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In some embodiments, the "alkylthio" moiety is represented by one of -S- alkyl, -S-alkenyl, and -S-alkynyl. Representative alkylthio groups include methylthio, and ethylthio. The term "alkylthio" also encompasses cycloalkyl groups, alkene and cycloalkene groups, and alkyne groups. "Arylthio" refers to aryl or heteroaryl groups. Alkylthio groups can be substituted as defined above for alkyl groups. [0992] The terms "alkenyl" and "alkynyl", refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively. In one embodiment, the alkenyl contains one double bond. In another embodiment, the alkenyl contains two double bonds. In another embodiment, the alkenyl contains three double bonds. [0993] The term "alkenylenyl" as used herein refers to a divalent radical of an alkenyl group. In one embodiment, the alkenylenyl is a divalent form of a C 2-12 alkenyl, i.e., a C 2 -C 12 alkenylenyl. In one embodiment, the alkenylenyl is a divalent form of a C 2-6 alkenyl, i.e., a C 2 - C 10 alkenylenyl. In one embodiment, the alkenylenyl is a divalent form of a C 2-14 alkenyl, i.e., a C 2 -C 8 alkenylenyl. In one embodiment, the alkylenyl is a divalent form of an unsubstituted C 2-6 alkenyl, i.e., a C 2 -C 6 alkenylenyl. In another embodiment, the alkylenyl is a divalent form of an unsubstituted C 2-4 alkyl, i.e., a C 2 -C 4 alkenylenyl. Non-limiting exemplary alkenylenyl groups include -CH=CH-, -CH 2 CH=CH-, -CH 2 CH 2 CH=CHCH 2 -, and -CH 2 CH=CHCH 2 CH=CHCH 2 CH 2 -. [0994] The terms "alkoxyl" or "alkoxy" as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, and tert-butoxy. An "ether" is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O-alkenyl, and -O- alkynyl. Aroxy can be represented by –O-aryl or O-heteroaryl, wherein aryl and heteroaryl are as defined below. The alkoxy and aroxy groups can be substituted as described above for alkyl. [0995] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the general formula: wherein R 9 , R 10 , and R' 10 each independently represent a hydrogen, an alkyl, an alkenyl, - (CH 2 ) m -R 8 or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R 8 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In some embodiments, only one of R 9 or R 10 can be a carbonyl, e.g., R 9 , R 10 and the nitrogen together do not form an imide. In still other embodiments, the term "amine" does not encompass amides, e.g., wherein one of R 9 and R 10 represents a carbonyl. In additional embodiments, R 9 and R 10 (and optionally R' 10 ) each independently represent a hydrogen, an alkyl or cycloalkly, an alkenyl or cycloalkenyl, or alkynyl. Thus, the term "alkylamine" as used herein means an amine group, as defined above, having a substituted (as described above for alkyl) or unsubstituted alkyl attached thereto, i.e., at least one of R 9 and R 10 is an alkyl group. [0996] The term "amido" is art-recognized as an amino-substituted carbonyl and includes a moiety that can be represented by the general formula: wherein R 9 and R 10 are as defined above. [0997] "Aryl", as used herein, refers to C 5 -C 10 -membered aromatic, heterocyclic, fused aromatic, fused heterocyclic, biaromatic, or bihetereocyclic ring systems. Broadly defined, "aryl", as used herein, includes 5-, 6-, 7-, 8-, 9-, and 10-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics". The aromatic ring can be substituted at one or more ring positions with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino (or quaternized amino), nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF 3 , -CN; and combinations thereof. [0998] The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (i.e., "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic ring or rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocycles. Examples of heterocyclic rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3 b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl. One or more of the rings can be substituted as defined above for "aryl". [0999] The term "aralkyl," as used herein, refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group). [1000] The term "carbocycle," as used herein, refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon. [1001] "Heterocycle" or "heterocyclic," as used herein, refers to a cyclic radical attached via a ring carbon or nitrogen of a monocyclic or bicyclic ring containing 3-10 ring atoms, for example, from 5-6 ring atoms, consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(Y) wherein Y is absent or is H, O, (C 1 -C 10 ) alkyl, phenyl or benzyl, and optionally containing 1-3 double bonds and optionally substituted with one or more substituents. Examples of heterocyclic rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxepanyl, oxetanyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H- pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl. Heterocyclic groups can optionally be substituted with one or more substituents at one or more positions as defined above for alkyl and aryl, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, and -CN. [1002] The term "carbonyl" is art-recognized and includes such moieties as can be represented by the general formula: wherein X is a bond or represents an oxygen or a sulfur, and R 11 represents a hydrogen, an alkyl, a cycloalkyl, an alkenyl, a cycloalkenyl, or an alkynyl, R' 11 represents a hydrogen, an alkyl, a cycloalkyl, an alkenyl, a cycloalkenyl, or an alkynyl. Where X is an oxygen and R 11 or R' 11 is not hydrogen, the formula represents an "ester". Where X is an oxygen and R 11 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R 11 is a hydrogen, the formula represents a "carboxylic acid". Where X is an oxygen and R' 11 is hydrogen, the formula represents a "formate". In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiocarbonyl" group. Where X is a sulfur and R 11 or R' 11 is not hydrogen, the formula represents a "thioester." Where X is a sulfur and R 11 is hydrogen, the formula represents a "thiocarboxylic acid." Where X is a sulfur and R' 11 is hydrogen, the formula represents a "thioformate." On the other hand, where X is a bond, and R 11 is not hydrogen, the above formula represents a "ketone" group. Where X is a bond, and R 11 is hydrogen, the above formula represents an "aldehyde" group. [1003] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Examples of heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur and selenium. Other useful heteroatoms include silicon and arsenic. [1004] As used herein, the term "nitro" means -NO 2 ; the term "halogen" designates -F, -Cl, - Br or -I; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; and the term "sulfonyl" means -SO 2 -. [1005] The term "substituted" as used herein, refers to all permissible substituents of the compounds described herein. In the broadest sense, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, but are not limited to, halogens, hydroxyl groups, or any other organic groupings containing any number of carbon atoms, for example, 1-14 carbon atoms, and optionally include one or more heteroatoms such as oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclic structural formats. Representative substituents include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C 3 -C 20 cyclic, substituted C 3 -C 20 cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, and polypeptide groups. [1006] As described herein, compounds of the present disclosure may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. [1007] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; —(CH 2 ) 0-4 R°; —(CH 2 ) 0-4 OR°; —O(CH 2 ) 0-4 R°, —O—(CH 2 ) 0-4 C(O)OR°; —(CH 2 ) 0-4 CH(OR°) 2 ; —(CH 2 ) 0-4 SR°; —(CH 2 ) 0-4 Ph, which may be substituted with R°; —(CH 2 ) 0-4 O(CH 2 ) 0-1 Ph which may be substituted with R°; —CH═CHPh, which may be substituted with R°; —(CH 2 ) 0-4 O(CH 2 ) 0-1 -pyridyl which may be substituted with R°; —NO 2 ; —CN; —N 3 ; —(CH 2 ) 0-4 N(R°) 2 ; —(CH 2 ) 0-4 N(R°)C(O)R°; —N(R°)C(S)R°; — (CH 2 ) 0-4 N(R°)C(O)NR° 2 ; —N(R°)C(S)NR° 2 ; —(CH 2 ) 0-4 N(R°)C(O)OR°; — N(R°)N(R°)C(O)R°; —N(R°)N(R°)C(O)NR° 2 ; —N(R°)N(R°)C(O)OR°; —(CH 2 ) 0-4 C(O)R°; — C(S)R°; —(CH 2 ) 0-4 C(O)OR°; —(CH 2 ) 0-4 C(O)SR°; —(CH 2 ) 0-4 C(O)OSiR° 3 ; —(CH 2 ) 0- 4 OC(O)R°; —OC(O)(CH 2 ) 0-4 SR°, SC(S)SR°; —(CH 2 ) 0-4 SC(O)R°; —(CH 2 ) 0-4 C(O)NR° 2 ; — C(S)NR° 2 ; —C(S)SR°; —SC(S)SR°, —(CH 2 ) 0-4 OC(O)NR° 2 ; —C(O)N(OR°)R°; — C(O)C(O)R°; —C(O)CH 2 C(O)R°; —C(NOR°)R°; —(CH 2 ) 0-4 SSR°; —(CH 2 ) 0-4 S(O) 2 R°; — (CH 2 ) 0-4 S(O) 2 OR°; —(CH 2 ) 0-4 OS(O) 2 R°; —S(O) 2 NR° 2 ; —(CH 2 ) 0-4 S(O)R°; — N(R°)S(O) 2 NR° 2 ; —N(R°)S(O) 2 R°; —N(OR°)R°; —C(NH)NR° 2 ; —P(O) 2 R°; —P(O)R° 2 ; — OP(O)R° 2; —OP(O)(OR°) 2 ; SiR° 3; —(C1-4 straight or branched alkylene)O—N(R°) 2 ; or — (C 1-4 straight or branched alkylene)C(O)O—N(R°) 2 , wherein each R° may be substituted as defined below and is independently hydrogen, C 1-6 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, — CH 2 -(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below. [1008] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, ( ) —(C 1-4 straight or branched alkylene) wherein each is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently selected from C 1-4 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include ═O and ═S. [1009] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: ═O, ═S, ═NNR* 2 , ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O) 2 R*, ═NR*, ═NOR*, —O(C(R* 2 )) 2-3 O—, or —S(C(R* 2 )) 2-3 S—, wherein each independent occurrence of R* is selected from hydrogen, C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted" group include: , wherein each independent occurrence of R* is selected from hydrogen, C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [1010] Suitable substituents on the aliphatic group of R* include halogen, , or — NO 2 , wherein each is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently C 1-4 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [1011] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include or — ; wherein each is independently hydrogen, C 1-6 aliphatic which may be substituted as defined below, unsubstituted —OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R , taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [1012] Suitable substituents on the aliphatic group of are independently halogen, , or —NO 2 , wherein each is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently C 1-4 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [1013] Heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. It is understood that "substitution" or "substituted" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation, for example, by rearrangement, cyclization, or elimination. [1014] In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein. The permissible substituents can be one or more and the same or different for appropriate organic compounds. The heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. [1015] In various embodiments, the substituent is selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone, each of which optionally is substituted with one or more suitable substituents. In some embodiments, the substituent is selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cycloalkyl, ester, ether, formyl, haloalkyl, heteroaryl, heterocyclyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone, wherein each of the alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cycloalkyl, ester, ether, formyl, haloalkyl, heteroaryl, heterocyclyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone can be further substituted with one or more suitable substituents. [1016] Examples of substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, thioketone, ester, heterocyclyl, –CN, aryl, aryloxy, perhaloalkoxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, alkylthio, oxo, acylalkyl, carboxy esters, carboxamido, acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl, arylamino, aralkylamino, alkylsulfonyl, carboxamidoalkylaryl, carboxamidoaryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy, aminocarboxamidoalkyl, cyano, alkoxyalkyl, perhaloalkyl, arylalkyloxyalkyl, and the like. In some embodiments, the substituent is selected from cyano, halogen, hydroxyl, and nitro. [1017] Antibodies: As used herein, the term "antibody" is referred to in the broadest sense and specifically covers various embodiments including, but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies formed from at least two intact antibodies), and antibody fragments (e.g., diabodies) so long as they exhibit a desired biological activity (e.g., "functional"). Antibodies are primarily amino-acid based molecules but may also comprise one or more modifications (including, but not limited to the addition of sugar moieties, fluorescent moieties, chemical tags, etc.). Non-limiting examples of antibodies or fragments thereof include VH and VL domains, scFvs, Fab, Fab', F(ab')2, Fv fragment, diabodies, linear antibodies, single chain antibody molecules, multispecific antibodies, bispecific antibodies, intrabodies, monoclonal antibodies, polyclonal antibodies, humanized antibodies, codon-optimized antibodies, tandem scFv antibodies, bispecific T-cell engagers, mAb2 antibodies, chimeric antigen receptors (CAR), tetravalent bispecific antibodies, biosynthetic antibodies, native antibodies, miniaturized antibodies, unibodies, maxibodies, antibodies to senescent cells, antibodies to conformers, antibodies to disease specific epitopes, or antibodies to innate defense molecules. [1018] Associated: As used herein, the terms "associated with," "conjugated," "linked," "attached," and "tethered," when used with respect to two or more moieties, means that the moieties are physically associated or connected with one another, either directly or via one or more additional moieties that serves as a linking agent, to form a structure that is sufficiently stable so that the moieties remain physically associated under the conditions in which the structure is used, e.g., physiological conditions. An "association" need not be strictly through direct covalent chemical bonding. It may also suggest ionic or hydrogen bonding or a hybridization based connectivity sufficiently stable such that the "associated" entities remain physically associated. [1019] Cargo: As used herein, the term "cargo" or "payload" can refer to one or more molecules or structures encompassed in a delivery vehicle for delivery to or into a cell or tissue. Non-limiting examples of cargo can include a nucleic acid, a polypeptide, a peptide, a protein, a liposome, a label, a tag, a small chemical molecule, a large biological molecule, and any combinations thereof. [1020] Chimeric Antigen Receptors (CARs): As used herein, the term "chimeric antigen receptor" or "CAR" refers to an artificial chimeric protein comprising at least one antigen specific targeting region (ASTR), a transmembrane domain and an intracellular signaling domain, wherein the antigen specific targeting region comprises a full-length antibody or a fragment thereof. Any molecule that is capable of binding a target antigen with high affinity can be used in the ASTR of a CAR. The CAR may optionally have an extracellular spacer domain and/or a co-stimulatory domain. A CAR may also be used to generate a cytotoxic cell carrying the CAR. [1021] Circular RNA: As used herein, the term "circular RNA" or "circRNA" refer to a RNA that forms a circular structure through covalent or non-covalent bonds. [1022] Co-Administered: As used herein, the term "co-administered" or "co-administering" means administering an originator construct, a benchmark construct or a targeting system with one or more additional an originator construct, a benchmark construct, a targeting systems or other therapeutic agents or moieties sufficiently close in time such that the effect of the originator construct, a benchmark construct, a targeting systems or other therapeutic agents or moieties is enhanced. [1023] Complementary and substantially complementary: As used herein, the term "complementary" refers to the ability of polynucleotides to form base pairs with one another. Base pairs are typically formed by hydrogen bonds between nucleotide units in antiparallel polynucleotide strands. Complementary polynucleotide strands can form base pair in the Watson-Crick manner (e.g., A to T, A to U, C to G), or in any other manner that allows for the formation of duplexes. As persons skilled in the art are aware, when using RNA as opposed to DNA, uracil rather than thymine is the base that is considered to be complementary to adenosine. However, when a U is denoted in the context of the present disclosure, the ability to substitute a T is implied, unless otherwise stated. Perfect complementarity or 100% complementarity refers to the situation in which each nucleotide unit of one polynucleotide strand can form hydrogen bond with a nucleotide unit of a second polynucleotide strand. Less than perfect complementarity refers to the situation in which some, but not all, nucleotide units of two strands can form hydrogen bond with each other. For example, for two 20-mers, if only two base pairs on each strand can form hydrogen bond with each other, the polynucleotide strands exhibit 10% complementarity. In the same example, if 18 base pairs on each strand can form hydrogen bonds with each other, the polynucleotide strands exhibit 90% complementarity. As used herein, the term "substantially complementary" means that the siRNA has a sequence (e.g., in the antisense strand) which is sufficient to bind the desired target mRNA, and to trigger the RNA silencing of the target mRNA. [1024] Delivery: As used herein, "delivery" refers to the act or manner of delivering a compound, substance, entity, moiety, cargo or payload. [1025] DNA and RNA: As used herein, the term "RNA" or "RNA molecule" or "ribonucleic acid molecule" refers to a polymer of ribonucleotides; the term "DNA" or "DNA molecule" or "deoxyribonucleic acid molecule" refers to a polymer of deoxyribonucleotides. DNA and RNA can be synthesized naturally, e.g., by DNA replication and transcription of DNA, respectively; or be chemically synthesized. DNA and RNA can be single-stranded (i.e., ssRNA or ssDNA, respectively) or multi-stranded (e.g., double stranded, i.e., dsRNA and dsDNA, respectively). The term "mRNA" or "messenger RNA", as used herein, refers to a single stranded RNA that encodes the amino acid sequence of one or more polypeptide chains. [1026] Encapsulate: As used herein, the term "encapsulate" means to enclose, surround or encase. [1027] Encode: As used herein the term "encode" refers broadly to any process whereby the information in a polymeric macromolecule is used to direct the production of a second molecule that is different from the first. The second molecule may have a chemical structure that is different from the chemical nature of the first molecule. [1028] Enhance expression of a gene: As used herein, the phrase "add-back" or "enhance expression of a gene" means to cause an increase in the amount of an expression product of the gene. The expression product can be an RNA transcribed from the gene (e.g., an mRNA) or a polypeptide translated from an mRNA transcribed from the gene. Typically, an increase in the level of an mRNA results in an increase in the level of a polypeptide translated therefrom. The level of expression may be determined using standard techniques for measuring mRNA or protein. [1029] Exosomes: As used herein, "exosome" is a vesicle secreted by mammalian cells or a complex involved in RNA degradation. [1030] Formulation: As used herein, a "formulation" includes at least one compound, substance, entity, moiety, cargo or payload and a delivery agent. [1031] Fragment: A "fragment," as used herein, refers to a portion. For example, fragments of proteins may comprise polypeptides obtained by digesting full-length protein isolated from cultured cells. [1032] Homology: As used herein, the term "homology" refers to the overall relatedness between polymeric molecules, e.g. between polynucleotide molecules (e.g. DNA molecules and/or RNA molecules) and/or between polypeptide molecules. In some embodiments, polymeric molecules are considered to be "homologous" to one another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical or similar. The term "homologous" necessarily refers to a comparison between at least two sequences (polynucleotide or polypeptide sequences). In accordance with the disclosure, two polynucleotide sequences are considered to be homologous if the polypeptides they encode are at least about 50%, 60%, 70%, 80%, 90%, 95%, or even 99% for at least one stretch of at least about 20 amino acids. In some embodiments, homologous polynucleotide sequences are characterized by the ability to encode a stretch of at least 4–5 uniquely specified amino acids. For polynucleotide sequences less than 60 nucleotides in length, homology is determined by the ability to encode a stretch of at least 4–5 uniquely specified amino acids. In accordance with the disclosure, two protein sequences are considered to be homologous if the proteins are at least about 50%, 60%, 70%, 80%, or 90% identical for at least one stretch of at least about 20 amino acids. [1033] Inactive Ingredient: As used herein, the term "inactive ingredient" refers to one or more agents that do not contribute to the activity of the active ingredient of the pharmaceutical composition included in formulations. In some embodiments, all, none or some of the inactive ingredients which may be used in the formulations of the present disclosure may be approved by the US Food and Drug Administration (FDA). [1034] IRES: As used herein, the term "internal ribosome entry site" or "IRES" refers to an RNA sequence or structural element ranging in size form 10 nucleotides to 1,000 nucleotides or more which is capable of initiating translation of a polypeptide in the absence of a normal RNA cap structure. [1035] Identity: As used herein, the term "identity" refers to the overall relatedness between polymeric molecules, e.g., between polynucleotide molecules (e.g. DNA molecules and/or RNA molecules) and/or between polypeptide molecules. Calculation of the percent identity of two polynucleotide sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second nucleic acid sequences for optimal alignment and non-identical sequences can be disregarded for comparison purposes). In certain embodiments, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the length of the reference sequence. The nucleotides at corresponding nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. For example, the percent identity between two nucleotide sequences can be determined using methods such as those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991; each of which is incorporated herein by reference. For example, the percent identity between two nucleotide sequences can be determined using the algorithm of Meyers and Miller (CABIOS, 1989, 4:11-17), which has been incorporated into the ALIGN program (version 2.0) using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The percent identity between two nucleotide sequences can, alternatively, be determined using the GAP program in the GCG software package using an NWSgapdna.CMP matrix. Methods commonly employed to determine percent identity between sequences include, but are not limited to those disclosed in Carillo, H. and Lipman, D., SIAM J Applied Math., 48:1073 (1988); incorporated herein by reference. Techniques for determining identity are codified in publicly available computer programs. Exemplary computer software to determine homology between two sequences include, but are not limited to, GCG program package, Devereux, J., et al., Nucleic Acids Research, 12(1), 387 (1984)), BLASTP, BLASTN, and FASTA Altschul, S. F. et al., J. Molec. Biol., 215, 403 (1990)). [1036] Inhibit expression of a gene: As used herein, the phrase "knock-down" or "inhibit expression of a gene" means to cause a reduction in the amount of an expression product of the gene. The expression product can be an RNA transcribed from the gene (e.g., an mRNA) or a polypeptide translated from an mRNA transcribed from the gene. Typically, a reduction in the level of an mRNA results in a reduction in the level of a polypeptide translated therefrom. The level of expression may be determined using standard techniques for measuring mRNA or protein. [1037] Ionizable Lipid: As used herein "ionizable lipid" refers to any of a number of lipid species that carry a net positive charge at a selected pH. [1038] Lipid Nanoparticle: As used herein "lipid nanoparticle" or "LNP" refers to a delivery vehicle comprising one or more lipids (e.g., cationic lipids, non-cationic lipids, PEG-modified lipids). [1039] Liposome: As used herein "liposome" generally refers to a vesicle composed of lipids (e.g., amphiphilic lipids) arranged in one or more spherical bilayers or bilayers. [1040] Modified: As used herein "modified" refers to a changed state or structure of a molecule. Molecules may be modified in many ways including chemically, structurally, and functionally. [1041] Non-Cationic Lipid: As used herein "non-cationic lipid" refers to any neutral, zwitterionic or anionic lipid. [1042] Peptide: As used herein, "peptide" is less than or equal to 50 amino acids long, e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 amino acids long. [1043] Pharmaceutical Composition: As used herein the term "pharmaceutical composition" refers to compositions comprising at least one active ingredient and optionally one or more pharmaceutically acceptable excipients. [1044] PEG: As used herein "PEG" means any polyethylene glycol or other polyalkylene ether polymer. [1045] Spacer: As used herein the term "spacer" refers to a region of a polynucleotide or polypeptide ranging from 1 residue to hundreds or thousands of residues separating two other elements in a sequence. The sequence of the spacer can be defined or random. A spacer sequence is typically non-coding but may be a coding sequence. [1046] Sterol: As used herein "sterol" is a subgroup of steroids consisting of steroid alcohols. [1047] Structural Lipid: As used herein "structural lipid" refers to sterols and lipids containing sterol moieties. [1048] Transcription: As used herein the term "transcription" refers to the formation or synthesis of an RNA molecule by an RNA polymerase using a DNA molecule as a template. [1049] Translation: As used herein the term "translation" refers to the formation of a polypeptide molecule by a ribosome based upon a RNA template. [1050] Treat and Prevent: As used herein the terms "treat" or "prevent" as well as words stemming therefrom do not necessarily imply 100% or complete treatment or prevention. Rather there are varying degrees of treatment or prevention of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. Also, "prevention" can encompass delaying the onset of the disease, symptom or condition thereof. [1051] Unmodified: As used herein, "unmodified" refers to any substance, compound or molecule prior to being changed in any way. Unmodified may, but does not always, refer to the wild type or native form of a biomolecule. Molecules may undergo a series of modifications whereby each modified molecule may serve as the "unmodified" starting molecule for a subsequent modification. [1052] Vector: As used herein, a "vector" is any molecule or moiety which transports, transduces or otherwise acts as a carrier of a heterologous molecule. Vectors of the present disclosure may be produced recombinantly and may be based on and/or may comprise viral parent or reference sequence. Such parent or reference viral sequences may serve as an original, second, third or subsequent sequence for engineering vectors. In non-limiting examples, such parent or reference viral sequences may comprise any one or more of the following sequences: a polynucleotide sequence encoding a polypeptide or multi-polypeptide, which sequence may be wild-type or modified from wild-type and which sequence may encode full-length or partial sequence of a protein, protein domain, or one or more subunits of a protein; a polynucleotide comprising a modulatory or regulatory nucleic acid which sequence may be wild-type or modified from wild-type; and a transgene that may or may not be modified from wild-type sequence . These viral sequences may serve as either the "donor" sequence of one or more codons (at the nucleic acid level) or amino acids (at the polypeptide level) or "acceptor" sequences of one or more codons (at the nucleic acid level) or amino acids (at the polypeptide level).The details of one or more embodiments of the disclosure are set forth in the accompanying description below. Although any materials and methods similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred materials and methods are now described. Other features, objects and advantages of the disclosure will be apparent from the description. In the description, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the case of conflict, the present description will control. XI. EXAMPLES Example 1. Methods of Making the Lipids [1053] The lipids of the present disclosure may be prepared using any convenient methodology. In a rational approach, the lipids are constructed from their individual components. The components can be covalently bonded to one another through functional groups, as is known in the art, where such functional groups may be present on the components or introduced onto the components using one or more steps, e.g., oxidation reactions, reduction reactions, cleavage reactions and the like. Functional groups that may be used in covalently bonding the components together to produce the lipids: hydroxy, sulfhydryl, amino, and the like. Where necessary and/or desired, certain moieties on the components may be protected using blocking groups, as is known in the art, see, e.g., Green & Wuts, Protective Groups in Organic Synthesis (John Wiley & Sons) (1991). [1054] Alternatively, the lipids can be produced using known combinatorial methods to produce large libraries of potential lipids which may then be screened for identification of a lipid with desired functionalities. Synthesis of Compound 5 Synthesis of 8-bromooctyl 2-((3r,5r,7r)-adamantan-1-yl)acetate (L30-2) [1055] To a solution of compound L30-1 (3.0 g, 15.4 mmol) in dichloromethane (100 mL) was added DMAP (1.89 g, 15.4 mmol), EDC (17.7 g, 92.6 mmol) and compound L29-4 (8.0 g, 38.6 mmol). The reaction mixture was stirred at room temperature for 12 h and reduced under vacuum. The residue was dissolved in dichloromethane (300 mL) and washed with brine (80 mL x 3). The organic phase was dried over anhydrous Na 2 SO 4 , the solvent was reduced under vacuum, and the crude was purified by column chromatography (330 g SiO 2 : 0 to 30% Ethyl acetate in Hexane gradient) to obtain compound L30-2 as colorless oil (4.5 g, 83%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.03 (t, 2H), 3.40 (t, 2H), 2.05 (s, 2H), 1.96-1.92 (m, 2H), 1.88-1.81 (m, 2H), 1.71-1.56 (m, 15H), 1.43-1.35 (m, 8H); CIMS m/z [M+H] + 385.3. Synthesis of nonyl 8-((8-(2-((3r,5r,7r)-adamantan-1-yl)acetoxy)octyl)(2-hydroxy ethyl) amino)octanoate (Compound 8) [1056] To a solution of compound L29-3 (0.35 g, 1.06 mmol) in CPME (10 mL) and CH 3 CN 10 mL), under nitrogen, was added compound L30-2 (0.37 g, 1.16 mmol), K 2 CO 3 (0.587 g, 4.2 mmol) and KI (0.176 g, 1.09 mmol). The reaction mixture was heated at 60 °C for 18 h. After cooling to room temperature, the reaction mixture was filtered through celite, washed with ethyl acetate, and the solvent removed under vacuum to give the crude product which was purified by flash chromatography (SiO2: 5% triethylamine in hexane/ ethyl acetate 0-25%) to obtain Compound 5 as colorless oil (0.33 g, 52%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.06-4.0 (m, 4H), 3.51 (t, 2H), 2.55 (t, 2H), 2.42 (t, 3H), 2.28 (t, 2H), 2.05 (s, 2H), 1.98-1.94 (m, 3H), 1.71- 1.57 (m, 18H), 1.43-1.25 (m, 32H), 0.87 (t, 3H)); CIMS m/z [M+H] + 634.1. Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 4.33 min, purity: > 97%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No.186005302),mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 10.16 min, purity: 90.2%. Synthesis of Compound 8 Synthesis of nonyl 8-bromooctanoate (L29-2) [1057] To a solution of compound L1-5 (3.0 g, 12.8 mmol) in dichloromethane (100 mL) was added DMAP (1.5 g, 12.8 mmol), EDC (9.86 g, 51.4 mmol) and L29-1 (4.08 g, 28.3 mmol). The reaction mixture was stirred at room temperature for 12 h and reduced under vacuum. The residue was dissolved in dichloromethane (300 mL) and washed with brine (80 mL x 3). The organic phase was dried over anhydrous Na 2 SO 4 , the solvent was reduced under vacuum, and the crude was purified by column chromatography (SiO 2 : 0 to 30% Ethyl acetate in Hexane gradient) to give compound L29-2 as colorless oil (2.5 g, 55%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.09 (t, 2H), 3.59 (t, 2H), 2.69 (t, 2H), 1.82-1.59 (m, 6H), 1.45-1.27 (m, 18H), 0.85 (t, 3H); CIMS m/z [M+H] + 349.3. Synthesis of nonyl 8-((2-hydroxyethyl)amino)octanoate (L29-3) [1058] To a solution of compound L29-2 (2.5 g, 7.1 mmol) in ethanol (40 mL) was added dropwise a solution of ethanolamine (6.55 g, 107 mmol) in EtOH (20 mL) at ambient temperature. The reaction solution was heated at 60 °C-70 °C for 12 h and concentrated in vacuo to give crude residue which was diluted with methyl tert-butyl ether (TBME). The TBME layer was separated from ethanolamine layer and the ethanolamine layer was back extracted with TBME (200 mL). The combined TBME layers were washed with 5% NaHCO 3 solution and then concentrated in vacuo at 40 °C to give the crude product which was purified by flash chromatography (SiO 2 : DCM/MeOH 0-100%, 1% NH 4 OH) to afford L29-3 as colorless oil (1.3 g, 55%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.02 (t, 2H), 3.61 (t, 2H), 2.72 (t, 2H), 2.57 (t, 2H), 2.46 (s, 2H), 2.25 (t, 2H), 1.66-1.40 (m, 6H), 1.35-1.13 (m, 18H), 0.84 (t, 3H); CIMS m/z [M+H] + 330.3. Synthesis of 8-bromooctyl 2-(bicyclo[1.1.1]pentan-1-yl)acetate (L29-6) [1059] To a solution of compound L29-5 (1.0 g, 7.9 mmol) in dichloromethane (30 mL) was added DMAP (0.97 g, 7.9 mmol, 1 eq) and EDC (6.0 g, 31.7 mmol) and compound L29-4 (3.6 g, 17.4 mmol). The reaction mixture was stirred at room temperature for 12 h and then concentrated under vacuum. The residue was dissolved in dichloromethane (300 mL) and washed with brine (80 mL x 3). The organic phase was dried over anhydrous Na 2 SO 4 , the solvent was reduced under vacuum, and the crude was purified by column chromatography (SiO 2 : 0 to 30% Ethyl acetate in Hexane gradient) to give compound L29-6 as colorless oil (0.75 g, 30%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.04 (t, 2H), 3.39 (t, 2H), 2.48-2.40 (m, 3H), 1.91-1.72 (m, 8H), 1.68-1.53 (m, 2H), 1-48-1.24 (m, 8H); CIMS m/z 317.5 [M+H] + 317.5. Synthesis of nonyl 8-((8-(2-(bicyclo[1.1.1]pentan-1-yl)acetoxy)octyl)(2- hydroxyethyl)amino)octanoate (8) [1060] To a solution of compound L29-3 (0.35 g, 1.06 mmol) in CPME (10 mL) and ACN (10 mL), under nitrogen, was added compound L29-6 (0.37 g, 1.16 mmol), K 2 CO 3 (0.587 g, 4.2 mmol) and KI (0.176 g, 1.09 mmol). The reaction mixture was heated at 80 °C for 18 h. After cooling to room temperature, the reaction mixture was filtered through celite, and washed with ethyl acetate. The combined filtrates were concentrated under vacuum to give the crude product which was purified by flash chromatography (SiO 2 : 5% triethylamine in hexane/ ethyl acetate 0-25%) to obtain compound 8 as colorless oil (0.31 g, 51%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.04 (t, 4H), 3.50 (t, 2H), 2.55 (t, 2H), 2.48-2.40 (m, 7H), 2.27 (t, 2H), 1.77 (s, 6H), 1.65-1.18 (m, 37H), 0.86 (t, 3H)); CIMS m/z [M+H] + 711.3. Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 7.62 min, purity: > 99%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No. 186005302),mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 9.37 min, purity: 94.4%. Synthesis of Compound 13 Synthesis of nonyl 8-((3-hydroxypropyl)amino)octanoate (L39-1) [1061] To a solution of compound L29-2 (1.5 g, 4.2 mmol) in ethanol (20 mL) was added a solution of propanolamine (4.8 g, 64.0 mmol) in EtOH (10 mL) at ambient temperature. The reaction solution was heated at 70 °C for 12 h and concentrated in vacuo at 40 °C to give crude residue. The crude residue was diluted with TBME and then the TBME layer was separated from the ethanolamine layer. The ethanolamine layer was extracted again with TBME (200 mL). The combined TBME layers were washed with 5% NaHCO 3 solution and then concentrated in vacuo at 40 °C to give pale yellow oil. The crude product was purified by flash chromatography (SiO2: DCM/MeOH 0-100%, 1% NH 4 OH) to obtain compound L39-1 as colorless oil (1.1 g, 74%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.03 (t, 2H), 3.63 (t, 2H), 2.70 (t, 2H), 2.58 (t, 2H), 2.46 (t, 2H), 2.24 (t, 2H), 1.62-1.41 (m, 6H), 1.36-1.14 (m, 20H), 0.85 (t, 3H); CIMS m/z 343.5 [M+H] + . Synthesis of nonyl 8-((8-(2-((3r,5r,7r)-adamantan-1-yl)acetoxy)octyl)(3-hydroxy propyl) amino)octanoate (L39-2) [1062] To a solution of compound L39-1 (1.0 g, 2.9 mmol) in CH 3 CN/CPME (1:1, 30 mL) under nitrogen, was added L30-2 (1.3 g, 3.5 mmol) and followed by the addition of K 2 CO 3 (1.6 g, 11.6 mmol) and KI (0.483 g, 2.9 mmol). The reaction mixture was heated at 100 °C for 18 h. After cooling to room temperature, the reaction mixture was filtered through celite, washed with ethyl acetate, and the solvent removed under vacuum to give the crude product which was purified by flash chromatography (SiO2: 5% triethylamine in hexane/ ethyl acetate 0-25%) to give L39-2 as colorless oil (1.2 g, 64%). 1 H-NMR (300 MHz, CDCl 3 ) δ 5.75 (s, 1H), 4.05-3.95 (m, 6H), 3.77 (t, 2H), 3.36 (t, 2H), 2.61 (t, 2H), 2.37 (t, 2H), 2.27 (t, 2H), 2.04 (s, 2H), 1.95 (s, 2H), 1.74-1.09 (m, 48H), 0.86 (t, 3H); CIMS m/z 698.1 [M+H] + . Synthesis of nonyl 8-((8-(2-((3r,5r,7r)-adamantan-1-yl)acetoxy)octyl)(3-hydroxy propyl) amino)octanoate (L39-3) [1063] To a solution of compound L39-2 (1.2 g, 1.85 mmol) in DCM (30 mL) under nitrogen was added MsCl (0.254 g, 2.2 mmol) and triethylamine (0.468 g, 4.62 mmol). The reaction mixture was stirred at room temperature for 2 h and reduced under vacuum. The residue was dissolved in dichloromethane (300 mL) and washed with brine (80 mL x 3). The organic phase was dried over anhydrous Na 2 SO 4 , the solvent was reduced under vacuum, and the crude L39- 3 was obtained as colorless oil (1.0 g, 74%) which was used for next step without further purification. Synthesis of (nonyl 8-((3-(1H-imidazol-1-yl)propyl)(8-(2-((3r,5r,7r)-adamantan-1 - yl)acetoxy)octyl)amino)octanoate) (Compound 13) [1064] To a solution of compound L39-3 (1.0 g, 1.37 mmol) in 2-propanol (30 mL) under nitrogen, imidazole (1.87 g, 27.5 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and then heated at 90 °C for 12 h. After cooling to room temperature, the reaction mixture was dissolved in dichloromethane (300 mL) and washed with brine (80 mL x 3). The organic phase was dried over anhydrous Na 2 SO 4, the solvent was removed under vacuum to give the crude product which was purified by flash chromatography (SiO2: DCM/MeOH 0-5%) to get Compound 13 as colorless oil (0.2 g, 20%). 1 H-NMR (300 MHz, CDCl 3 ) δ 7.46 (s, 1H), 7.04 (s, 1H), 6.91 (s, 1H), 4.06-3.97 (m, 6H), 2.59-2.35 (m, 6H), 2.27 (t, 2H), 2.04 (s, 2H), 1.98-1.89 (m, 5H), 1.74-1.59 (m, 18H), 1.40-1.12 (m, 30H), 0.86 (t, 3H); CIMS m/z [M+H] + 698.51. Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 8.33 min, purity: > 99%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No. 186005302),mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 8.01 min, purity: 86.4%. Synthesis of Compound 21 Synthesis of 2-(tetradecylthio)ethan-1-ol (L40-2) [1065] To a solution of L40-1 (7 g, 1 eq) in DMF (50 mL) was added K 2 CO 3 (7 g, 2 eq) followed by the addition of 2-mercaptoethan-1-ol (2 mL, 1.2 eq). The resulting mixture was stirred for 16 hours at room temperature. The reaction mixture was then filtered through filter paper and the filter cake was rinsed with DCM (30 mL). The organic fraction was reduced under vacuum to obtain crude product which was subjected to silica gel column using 0 – 20% EA in hexane as eluent to afford L40-2 as white solid (5.7g, 85%). 1 H-NMR (300 MHz, CDCl 3 ) δ 3.70 (q, 2H), 2.72 (t, 2H), 2.50 (t, 2H), 2.14 (m, 1H), 1.54-1.59 (m, 2H), 1.34-1.25 (m, 22H), 0.87 (t, 3H). Synthesis of 2-(tetradecylthio)ethyl acrylate (L40-3) [1066] The starting material L40-2 (2 g,1 eq) and triethylamine (1.6 mL, 1.5 eq) were dissolved in DCM (40 mL). The solution was cooled to 0 °C and acryloyl chloride (800 μL, 1.2 eq) was added in dropwise. The reaction mixture was then allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with H 2 O (100 mL) and brine (100mL). The organic layer was dried over Na 2 SO 4 and reduced under vacuum to obtain crude product which was subjected to silica gel column using 0 – 10% EA in hexane as eluent to afford L40- 3 as colorless oil (1.6 g, 70%). 1 H-NMR (300 MHz, CDCl 3 ) δ 6.40 (dd, 1H), 6.07-6.16 (qd, 1H), 5.82 (dd, 1H), 4.29 (t, 2H), 2.76 (t, 2H), 2.55 (t, 2H), 1.54-1.59 (m, 2H), 1.34-1.25 (m, 22H), 0.87 (t, 3H). Synthesis of 8-((3-(1H-imidazol-1-yl)propyl)amino)octyl 2-((3r,5r,7r)-adamantan-1- yl)acetate (L40-4) [1067] 1-(3-Aminopropyl)imidazole (1.74 g, 10 eq) was dissolved in ethanol, followed by adding the starting material L30-2 (500 mg, 1 eq). The reaction mixture was stirred at 80 °C for 16 hours. When TLC showed completion of the reaction, the solvent was reduced under vacuum and the crude product was dissolved in a small amount of DCM and subjected to silica gel column using 0 – 40% MeOH in DCM with 2% NH 3 ∙H 2 O as eluent to afford L40-4 as colorless oil (360 mg, 60%). 1 H-NMR (300 MHz, CDCl 3 ) δ 7.58 (s, 1H), 7.14 (s, 1H), 6.86 (s, 1H), 4.00-3.96 (m, 4H), 2.50-2.37 (m, 4H), 2.02 (s, 2H), 1.91 (bs, 3H), 1.82-1.77 (m, 2H), 1.76-1.48 (m, 12H), 1.40-1.20 (m, 9H); CIMS m/z [M+H] + 430.3. Synthesis of 2-(tetradecylthio)ethyl 3-((3-(1H-imidazol-1-yl)propyl)(8-(2-((3r,5r,7r)- adamantan-1-yl)acetoxy)octyl)amino)propanoate (Compound 21) [1068] The starting materials L40-4 (360 mg, 1.2 eq) and L40-3 (229 mg, 1 eq) obtained from previous steps were mixed in a round bottom flask. The reaction was stirred at 90 °C for 24 hours. The reaction mixture was then subjected to silica gel column using 0 – 6% MeOH in DCM as eluent to afford Compound 21 (254 mg, 48%) as light-yellow oil. 1 H-NMR (300 MHz, DMSO-d 6 ) δ, 7.58 (s, 1H), 7.14 (s, 1H), 6.87 (s, 1H), 4.13 (t, 2H), 4.04-3.84 (m, 4H), 2.69 (t, 2H), 2.63 (t, 2H), 2.37 (t, 2H), 2.32-2.22 (m, 4H), 2.02 (s, 2H), 1.91 (bs, 3H), 1.84-1.72 (m, 2H), 1.71-1.42 (m, 18H), 1.38-1.12 (m, 36H), 0.85 (t, 3H); CIMS m/z [M+H] + 758.6. Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 5.94 min, purity: 99.2%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No. 186005302), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 20 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 6.98 min, purity: 98.0%. Synthesis of Compound 51 Synthesis of 3-pentyloctyl 8-((4-hydroxybutyl)amino)octanoate (L32-1) [1069] To a solution of 3-pentyloctyl 8-bromooctanoate L1-6 (6.0 g, 14.8 mmol) in ethanol (120 mL) was added 4-aminobutanol (13.1 g, 148.1 mmol). The resulting mixture was heated to 65-70°C and stirred overnight. The reaction mixture was then concentrated. DCM (250 mL) was added to the residue. The solution was washed with water (100 mL), brine and dried over Na 2 SO 4. Concentration under reduced pressure gave crude product, which was purified flash chromatography (SiO 2 : 0 to 10% MeOH in DCM (1% NH 4 OH) gradient) to yield L32-1 as colorless oil (4.44 g, 72%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.06 (t, 2H), 3.56 (t, 2H), 2.57-2.64 (m, 4H), 2.26 (t,2H), 1.49-1.67 (m, 11H), 1.24-1.30 (m, 24H), 0.87 (t, 6H); CIMS m/z [M+H] + 414.4. Synthesis of 8-bromooctyl 2-(bicyclo[2.2.2]octan-1-yl)acetate (L32-3) [1070] To a solution of compound L32-2 (1.0 g, 5.9 mmol) in dichloromethane (20 mL) was added DMAP (0.729 g, 5.9 mmol), EDC (4.55 g, 23.7 mmol) and L29-4 (2.73 g, 13.0 mmol). The reaction mixture was stirred at room temperature for 12 h and reduced under vacuum. The residue was dissolved in dichloromethane (300 mL) and washed with brine (80 mL x 3). The organic phase was dried over anhydrous Na 2 SO 4 , the solvent was removed under vacuum and the crude product was purified by flash chromatography (SiO 2 : 0 to 30% Ethyl acetate in Hexane gradient) to get product L32-3 as colorless oil (0.72 g, 33%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.08 (t, 2H), 3.55 (t, 2H), 2.09 (s, 2H), 1.80 (m, 2H), 1.61-1.24 (m, 23H); CIMS m/z [M+H] + 359.3. Synthesis of 3-pentyloctyl 8-((8-(2-(bicyclo[2.2.2]octan-1-yl)acetoxy)octyl)(4- hydroxybutyl)amino)octanoate (Compound 51) [1071] To a solution of compound L32-1 (0.33 g, 0.79 mmol) in CH 3 CN/CPME (1:1, 10 mL) under nitrogen, was added compound L32-3 (0.315 g, 0.87 mmol), followed by the addition of K 2CO3 (0.44 g, 3.1 mmol) and KI (0.13 g, 0.79 mmol). The reaction mixture was heated at 60 °C for 18 h. After cooling to room temperature, the reaction mixture was filtered through celite, washed with ethyl acetate, and the solvent removed under vacuum to give the crude product, which was purified by flash chromatography (SiO 2 : 5% triethylamine in hexane/ ethyl acetate 0-25%) to obtain Compound 51 as colorless oil (0.25 g, 45%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.09-3.98 (m, 4H), 3.59-3.38 (m, 2H), 2.51-2.39 (m, 6H), 2.27 (t, 2H), 2.03 (s, 2H), 1.72-1.15 (m, 61H), 0.87 (t, 6H)); CIMS m/z [M+H] + 692.6. Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 8.36 min, purity: > 96%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No. 186005302),mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 12.95 min, purity: > 85.4%.
Synthesis of Compound 52 Synthesis of 8-bromooctyl 2-((2r,3r,5r,6r,7r,8r)-cuban-1-yl)acetate (L33-2): [1072] A mixture of L33-1 (990 mg, 6.165 mmol), EDC (4.68 g, 24.41 mmol) and DMAP (820.3 mg, 6.71 mmol) in dichloromethane (20 mL) was stirred at room temperature for 10 min. L29-4 (1.91g, 9.15 mmol) was added and the resulting mixture was stirred at room temperature for 4h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (SiO 2 : ethyl acetate/hexane 0-10%) to give Compound L33-2 (1.81 g, 84%) as slightly yellow oil. 1 H NMR (300 MHz, CDCl 3 ): δ ppm 4.07 - 4.02 (m, 3H), 3.98 - 3.81 (m, 6H), 3.39 (t, J =7.0 Hz, 2H), 2.63(s, 2H), 1.87-1.79 (m, 2H), 1.60-1.54 (m, 2H), 1.43-1.31 (m, 8H). MS (CI): m/z [M+H] + 354.42 Synthesis of 3-pentyloctyl 8-((8-(2-((2r,3r,5r,6r,7r,8r)-cuban-1-yl)acetoxy)octyl)(4-hy droxy butyl)amino)octanoate (52): [1073] A mixture of L33-2 (600 mg, 1.69 mmol), L32-1 (351.3 mg, 0.849 mmol), KI (423 mg, 2.55 mmol) and potassium carbonate (704 mg, 5.09 mmol) in anhydrous ACN (5 mL) and cyclopentylmethyl ether (CPME) (5mL) was stirred at 90 °C for 36h. After cooling to room temperature, the reaction mixture was filtered through celite. The celite cake was washed with ACN (15 ml). The combined filtrates were concentrated. The obtained crude was purified by flash chromatography (SiO 2 : ethyl acetate/hexane 0-50%, the flash column was equilibrated with 10% triethylamine in hexane for 15 min before use) to give Compound 52 (770 mg, 66%). 1H NMR (300 MHz, CDCl 3 ): δ ppm 6.7 (bs, 1H), 4.07-4.0 (m, 6H), 3.98-3.81 (m, 6H), 3.61 (t, J =2.0 Hz, 2H), 2.63(s, 2H), 2.43-2.2.39 (m, 6H), 2.31 (t, J =5.0 Hz, 2H), 1.65-1.19(m, 44H), 0.85(t, J = 7.0 Hz, 6H). MS (CI): m/z [M+H] + 687.09. Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mmol, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 10.7 min, purity: >90.72%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No.186005302),mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 13.1 min, purity: 97.3%. Synthesis of Compound 53 Synthesis of ((3-pentyloctyl 8-((8-(2-(bicyclo[1.1.1]pentan-1-yl)acetoxy)octyl)(4- hydroxybutyl)amino)octanoate) (Compound 53) [1074] To a solution of compound L32-1 (0.35 g, 0.84 mmol) in CH 3 CN/CPME (1:1, 10 mL) under nitrogen was added L29-6 (0.322 g, 1.01 mmol), followed by the addition of K 2 CO 3 (0.467 g, 3.3 mmol) and KI (0.14 g, 0.84 mmol). The reaction mixture was heated at 100 °C for 18 h. After cooling to room temperature, the reaction mixture was filtered through Celite, washed with ethyl acetate, and the solvent removed under vacuum to give the crude product which was purified by flash chromatography (SiO 2 : 5% triethylamine in hexane/ ethyl acetate 0-25%) to obtain Compound 53 as colorless oil (0.315 g, 57%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.06 (t, 4H), 3.59-348 (m, 2H), 2.46-2.38 (m, 8H), 2.26 (t, 2H), 1.77 (s, 6H), 1.63-1.08 (m, 47H), 0.86 (t, 6H)); CIMS m/z [M+H] + 650.5. Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 6.66 min, purity: > 99%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No. 186005302),mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 7.52 min, purity: > 94.1%. Synthesis of Compound 55 Synthesis of (1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 8-bromooctanoate (L36-2) [1075] To a solution of 1R-(+)-Borneol L36-1 (1.0 g, 6.49 mmol), 8-bromo octanoic acid L1- 5 (1.73 g, 7.78 mmol) and DMAP (395 mg, 3.24 mmol) in DCM (20 mL) was added EDC (2.97 g, 15.5 mmol) at room temperature and the resulting mixture was stirred under nitrogen atmosphere overnight. The reaction mixture was concentrated to half the volume and purified by flash chromatography (SiO 2 : 0 to 5% ethyl acetate in hexane gradient) to yield L36-2 as colorless oil (1.7 g, 73%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.86 (m, 1H), 3.37-3.52 (m, 2H), 2.31 (m, 3H), 1.6-1.87 (m, 8H), 1.25-1.43 (m, 8H), 0.8-0.89 (m, 9H). Synthesis of 3-pentyloctyl 8-((4-hydroxybutyl)(8-oxo-8-(((1R,2S,4R)-1,7,7-trimethylbicy clo [2.2.1]heptan-2-yl)oxy)octyl)amino)octanoate (Compound 55) [1076] To a solution of L32-1 (500 mg, 1.21 mmol) and L36-2 (520 mg, 1.45 mmol) in a mixture of AcCN/CPME (1:1, 10 mL) under nitrogen was added K 2 CO 3 (500 mg, 3.63 mmol) and KI (100 mg, 0.605 mmol). The reaction mixture was heated at 75°C overnight under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered through celite. The filtrate was concentrated to give crude product, which was purified by flash chromatography (SiO 2 : 0 to 5% MeOH in DCM gradient) to yield Compound 55 as colorless oil (397 mg, 47%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.87 (m, 1H), 4.06 (t, J = 7.14 Hz, 2H), 3.55 (m, 2H), 2.48 (m, 6H), 2.27 (m, 4H), 1.92 (m, 1H), 1.52-1.73 (m, 16H), 1.18-1.3 (m, 34H) 0.81-0.89 (m, 15H); CIMS m/z [M+H] + 692.6. Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 6.67 min, purity: > 99%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No. 186005302),mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 9.16 min, purity: > 99 %. Synthesis of Compound 56 Synthesis of 1-(3-pentyloctyl) 17-((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) 9- oxoheptadecanedioate (L44-1): [1077] A mixture of L43-1 (780 mg, 1.57 mmol), EDC (1.2 g, 6.28 mmol), DMAP (192 mg, 1.57 mmol) and (S)-borneol (484.38 mg, 3.14 mmol) in anhydrous dichloromethane (30mL) was stirred at room temperature for 4h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (SiO 2 : ethyl acetate/hexane 0- 20%) to afford L44-1 (542 mg, 55%) as slightly yellow oil. 1 H NMR (300 MHz, CDCl 3 ): δ ppm 4.86 (d, J =8.0 Hz, 1H), 4.07 (t, J = 7.0 Hz, 2H), 2.40-2.1 (m, 8H), 1.96-1.87 (m, 1H), 1.79-1.46 (m, 12H), 1.39-1.12 (m, 33H), 1.05-0.83 (m, 12H), 0.81 (s, 3H); MS (CI) : m/z [M+H] + 634.12. Synthesis of 1-(3-pentyloctyl) 17-((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) 9- hydroxyheptadecanedioate (L44-2): [1078] To a mixture of L44-1 (540 mg, 0.853 mmol) in anhydrous THF (10 mL) and anhydrous MeOH (10 mL) was added sodium borohydride (42 mg, 1.1 mmol) at 0°C. The resulting mixture was then stirred at room temperature for 2h. The reaction was quenched with HCl (1 M), and all the volatile components were reduced under vacuum. The residue was dissolved in diethyl ether and washed with H 2 O and brine. The organic phase was dried over Na 2 SO 4 and reduced under vacuum to obtain crude material which was purified by silica gel column chromatography (ethyl acetate/hexane 0-20%) to get Compound L44-2 (490 mg, 90.5%) as slightly yellow oil. 1 H NMR (300 MHz, CDCl 3 ): δ ppm 4.88 (d, J =8.0 Hz, 1H), 4.07 (t, J = 7.0 Hz, 2H), 3.56(s, 1H), 2.34-2.21 (m, 6H), 1.98-1.89 (m, 1H), 1.79-1.51 (m, 9H), 1.49-1.18 (m, 36H), 0.96-0.86 (m, 12H), 0.82 (s, 3H); MS (CI) : m/z [M+H] + 636.12. Synthesis of 1-(3-pentyloctyl) 17-((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) 9- ((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (Compound 56): [1079] A mixture of dimethylamino butanoic acid (155.2 mg, 0.93 mmol), EDC (592 mg, 3.09 mmol) and DMAP (94.3 mg, 0.77 mmol) in anhydrous dichloromethane (10mL) was stirred at room temperature for 10 min. A solution of L44-2 (490 mg, 0.77 mmol) in anhydrous dichloromethane (5 mL) was added in and the resultant mixture was stirred at room temperature for 4h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (the flash column was equilibrated with 10% triethylamine in hexane before use, eluent: ethyl acetate/hexane 0-50%) to give Compound 56 (551 mg, 96%). 1 H NMR (300 MHz, CDCl 3 ): δ ppm 4.88 (d, J =8.0 Hz, 1H), 4.07 (t, J = 7.0 Hz, 2H), 2.44-2.20 (m, 16H), 1.98-1.23 (m, 52H), 0.90-0.80 (m, 15H); MS (CI): m/z [M+H] + 749.21 Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mmol, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 10.7 min, purity: 96.93%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No. 186005302),mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 13.1 min, purity: >99%. Synthesis of Compound 57 Synthesis of 3-pentyloctyl 8-((2-hydroxyethyl)amino)octanoate (L31-1) [1080] To a mixture of 3-pentyloctyl 8-bromooctanoate L1-6 (2.55 g, 6.29 mmol) in ethanol (40 mL) was added 2-aminoethanol (3.83 g, 62.9 mmol) and the reaction mixture was heated to 65-70°C and stirred overnight. The reaction mixture was concentrated, and DCM (150 mL) was added to the residue. After washed with water and brine, the organic phase was dried over Na 2 SO 4 and concentrated under reduced pressure to give crude product, which was purified by flash chromatography (SiO 2 : 0 to 10% MeOH in DCM (1% NH 4 OH) gradient) to yield L31-1 as colorless oil (1.55 g, 64%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.07 (t, J = 7.14 Hz, 2H), 3.65 (t, J = 5.22 Hz, 2H), 2.79 (t, J = 5.22 Hz, 2H), 2.62 (t, J = 7.14 Hz, 2H), 2.48 (m, 2H), 2.27 (t, J = 7.44 Hz, 2H), 1.48-1.6 (m, 5H), 1.17-1.31 (m, 24H) 0.87 (t, J = 6.33 Hz, 6H); CIMS m/z [M+H] + 386.3. Synthesis of 3-pentyloctyl 8-((8-(2-((3r,5r,7r)-adamantan-1-yl)acetoxy)octyl)(2- hydroxyethyl) amino)octanoate (Compound 57) [1081] To a solution of L31-1 (446 Mg, 1.08 mmol) and L30-2 in AcCN/CPME (1:1, 10 mL) under nitrogen was added K 2 CO 3 (447 mg, 3.24 mmol) and KI (90 mg, 0.54 mmol). The reaction mixture was heated at 80°C overnight under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered through celite and the celite cake was washed with acetonitrile. The filtrate was concentrated to give crude product, which was purified by flash chromatography (SiO 2 : 0 to 10% MeOH in DCM (1% NH 4 OH) gradient) to yield 57 as colorless oil (505 mg, 68%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.05 (m, 4H), 3.62 (m, 2H), 2.69 (m, 2H), 2.56 (m, 4H), 2.27 (t, J = 7.4 Hz, 2H), 2.05 (s, 2H), 1.96 (m, 3H), 1.55-1.63 (m, 22H), 1.24-1.38 (m, 32H), 0.87 (m, J = 7.14 Hz, 6H); CIMS m/z [M+H] + 690.5. Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 9.28 min, purity: > 99%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No.186005302),mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 9.37 min, purity: 94.69 %. Synthesis of Compound 58 Synthesis of 3-pentyloctyl 8-((3-hydroxypropyl)amino)octanoate (L38-1) [1082] To a solution of L1-6 (1.35 g, 3.33 mmol) in ethanol (25 mL) was added 3- aminopropanol (2.49 g, 33.3 mmol). The reaction mixture was heated to 70°C and stirred overnight. The reaction mixture was concentrated, and DCM (100 mL) was added to the residue. After washed with water (50 mL), brine (50 mL) and dried over Na 2 SO 4 , the organic phase was concentrated under reduced pressure to give crude product, which was purified by flash chromatography (SiO 2 : 0 to 10% MeOH in DCM (1% NH 4 OH) gradient) to yield L38-1 as colorless oil (870 mg, 65%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.06 (t, J = 6.87 Hz, 2H), 3.8 (t, J = 5.4 Hz, 2H), 2.87 (t, J = 5.79 Hz, 2H), 2.58 (t, J = 7.14 Hz, 2H), 2.27 (t, J = 7.41 Hz, 2H), 1.54-1.69 (m, 7H), 1.24-1.29 (m, 26H) 0.87 (t, J = 6.6 Hz, 6H); CIMS m/z [M+H] + 400.4. Synthesis of 3-pentyloctyl 8-((8-(2-((3r,5r,7r)-adamantan-1-yl)acetoxy)octyl)(3-hydroxy propyl)amino) octanoate (L38-2) [1083] To a solution of L38-1 (870 Mg, 2.18 mmol) and L30-2 (1.0 g, 2.61 mmol) in ACN/CPME (1:1, 20 mL) under nitrogen was added K 2 CO 3 (900 mg, 6.54 mmol) and KI (180 mg, 1.09 mmol). The reaction mixture was heated at 80°C overnight under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered through celite and the celite cake was washed with acetonitrile. The filtrate was concentrated to give crude product, which was purified by flash chromatography (SiO 2 : 0 to 6% MeOH in DCM gradient) to yield L38-2 as colorless oil (1.08 g, 70%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.05 (m, 4H), 3.79 (m, 2H), 2.67 (m, 2H), 2.43 (m, 4H), 2.27 (t, J = 7.4 Hz, 2H), 2.05 (s, 2H), 1.96 (m, 2H), 1.55- 1.68 (m, 20H), 1.5 (m, 3H), 1.24 (m, 34H), 0.87 (t, J = 6.6 Hz, 6H); CIMS m/z [M+H] + 704.6. Synthesis of 3-pentyloctyl 8-((8-(2-((3r,5r,7r)-adamantan-1-yl)acetoxy)octyl)(3- ((methylsulfonyl)oxy) propyl)amino)octanoate (L38-3) [1084] To a solution of L38-2 (1.08 g, 1.53 mmol) in anhydrous DCM (15 mL) was added methanesulfonyl chloride (141 μL, 1.83 mmol) and triethylamine (385 mL, 3.82 mmol)) at room temperature. The solution was stirred at room temperature for 1 hour. Reaction mixture was diluted with DCM (75 mL) and washed with water (2 x 50 mL) and brine (50 mL). The organic layer was dried over Na 2 SO 4, and solvent was reduced under vacuum. The crude product L38-3 was dried under high vacuum for 1 hour and used for next step without further purification and characterization. Synthesis of 3-pentyloctyl 8-((3-(1H-imidazol-1-yl)propyl)(8-(2-((3r,5r,7r)-adamantan-1 - yl)acetoxy) octyl)amino)octanoate (Compound 58) [1085] To a solution of crude L38-3 in isopropanol (15 mL) was added imidazole (2.0 g, 30.6 mmol). The reaction mixture was stirred at 90 °C under nitrogen overnight. The solvent was reduced under vacuum, and the residue was dissolved in DCM (75 mL) and washed with water (2 x 50 mL). Organic layer was dried over Na 2 SO 4, and solvent was reduced under vacuum. Crude product was purified by flash chromatography (SiO 2 : 0 to 5% MeOH in DCM gradient) to yield Compound 58 as light-yellow oil (870 mg, 75%). 1 H-NMR (300 MHz, CDCl 3 ): 7.45 (s, 1H), 7.04 (s, 1H), 6.9 (s, 1H), δ 4.03 (m, 6H), 2.32 (m, 8H), 2.05 (s, 2H), 1.96 (m, 3H), 1.85 (m, 1H), 1.6 (m, 20H), 1.28 (m, 34H), 0.87 (m, 6H); CIMS m/z [M+H] + 754.6. Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 5.78 min, purity: > 99.59%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No.186005302),mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 6.52 min, purity: 95.69 %. Synthesis of Compound 59 Synthesis of 1-((1R,5S)-bicyclo[3.2.1]octan-6-yl) 17-(3-pentyloctyl) 9-oxoheptadecanedioate (L46-1) [1086] A mixture of L43-1 (700 mg, 1.41 mmol), EDC (1.08 g, 5.65 mmol), DMAP (173 mg, 1.41 mmol) and L35-1 (436 mg, 2.82 mmol) in anhydrous dichloromethane (25 mL) was stirred at room temperature for 4h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (SiO 2 : ethyl acetate/hexane 0-20%) to afford L46-1 (510 mg, 60%) as colorless oil. 1 H-NMR (300 MHz, CDCl 3 ) δ 4.95 (m, 1H), 4.07 (t, 2H), 2.39–2.23 (m, 9H), 2.08–2.01 (m, 2H), 1.80–1.18 (m, 48H), 0.88 (t, 6H). Synthesis of 1-((1R,5S)-bicyclo[3.2.1]octan-6-yl) 17-(3-pentyloctyl) 9-hydroxyhepta decanedioate (L46-2) [1087] To a mixture of L46-1 (510 mg,0.805 mmol) in anhydrous THF (10 mL) and anhydrous MeOH (10 mL) was added sodium borohydride (37 mg, 1.0 mmol) at 0°C. The resulting mixture was then stirred at room temperature for 2h. The reaction was quenched with HCl (1 M), and all the volatile components were reduced under vacuum. The residue was dissolved in diethyl ether and washed with H 2 O and brine. The organic phase was dried over Na 2 SO 4 and reduced under vacuum to obtain crude material which was purified by silica gel column chromatography (ethyl acetate/hexane 0-20%) to get Compound L46-2 (320 mg, 63%) as light brown oil. 1 H-NMR (300 MHz, CDCl 3 ) δ 4.95 (m, 1H), 4.07 (t, 2H), 3.57 (bs, 1H), 2.30–2.20 (m, 5H), 2.08–1.99 (m, 2H), 1.80–1.18 (m, 48H), 0.88 (t, 6H). Synthesis of 1-((1R,5S)-bicyclo[3.2.1]octan-6-yl) 17-(3-pentyloctyl) 9-((4-(dimethylamino) butanoyl) oxy)heptadecanedioate (Compound 59) [1088] A mixture of dimethylamino butanoic acid (81 mg, 0.5 mmol), EDC (319 mg, 1.66 mmol) and DMAP (51.2 mg, 0.42 mmol) in anhydrous dichloromethane (8 mL) was stirred at room temperature for 10 min. A solution of L46-2 (300 mg, 0.42 mmol) in anhydrous dichloromethane (5 mL) was added and the resultant mixture was stirred at room temperature for 4h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (the flash column was equilibrated with 10% triethylamine in hexane before use, eluent: ethyl acetate/hexane 0-50%) to give Compound 59 (620 mg, 62%) as light brown oil. 1 H-NMR (300 MHz, CDCl 3 ) δ 4.96–4.82 (m, 2H), 4.07 (t, 2H), 2.32–2.22 (m, 15H), 2.08–1.99 (m, 2H), 1.82–1.10 (m, 62H), 0.87 (t, 6H); CIMS m/z 720.6 [M+1]; Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 8.75 min, purity: >99 %. UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No.186005302), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 11.57 min, purity: 90.45 %.
Synthesis of Compound 60 Synthesis of 2-(9-bromononyl)-1,7,7-trimethylbicyclo [2.2.1] heptane (L37-2) [1089] To a DCM (30 ml) solution of L37-1 (2.0 g, 12.98 mmol, 1.0 eq) and bromo-acid L1- 5 (3.74 g, 16.88 mmol, 1.3 eq) was added EDC (7.44 g, 38.96 mmol, 3.0 eq) and DMAP (792 mg, 6.44 mmol). The solution was stirred for 3 h at room temperature and then concentrated under reduced pressure. The crude was purified by flash chromatography (solvent: 0-10% EA in Hexane) to give L37-2 as color less oil (3.21 g, 68.7 %). 1 H-NMR (300 MHz, CHCl 3 ) δ: 4.85-4.90 (dd, 1H), 3.37-3.39 (t, 1H), 2.28-2.30 (t, 2H), 1.35 to 1.84 (m, 6H), 1.24-1.35 (m, 7H), 0.81 to 0.89 (3S, 9H). Synthesis of 3-pentyloctyl 8-((4-hydroxybutyl) (8-oxo-8-(((1S,2R,4S)-1,7,7-trimethylbicyclo [2.2.1] heptan-2-yl) oxy) octyl) amino) octanoate (Compound 60) [1090] A mixture of L32-1 (750 mg, 1.82 mmol, 1.0 eq), L37-2 (750 mg, 2.3 mmol), potassium carbonate (150 mg, 0.9 mmol) and KI (150 mg, 0.9 mmol) with CPME (15 ml) and ACN (15 ml) was heated to 80°C for 18 h. After cooling to room temperature, the reaction mixture was filtered through celite. The celite plug was washed with ACN (150ml). The filtrate was concentrated. The crude material was purified by column chromatography (Solvent: 0-10% MeOH in DCM) to give Compound 60 as a colorless oil (390 mg, 32.6%). 1 HNMR (CDCl 3 ) δ: 0.8091- 0.8896 (m, 15H), 1.239- 1.299 (m, 22 H), 1.543 – 1.567(m, 1H), 1.540 – 1.550 (m, 9H), 2.241 – 2.320 (q, 4H), 2.500 – 2.650 (bs, 4H), 3.567 (s, 1H), 4.038-4.086 (t, 1H), 4.89- 4.990 (d, 1H); CIMS m/z [M+H] + 692.7; CIMS m/z [M+H] + 634.1. Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 7.10 min, purity: > 99%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No.186005302),mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 8.92 min, purity: 97.6%. Synthesis of Compound 62 Synthesis of 1-(3-pentyloctyl) 17-(1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) 9-oxohepta decanedioate (L43-2): [1091] A mixture of L43-1 (230 mg, 0.46 mmol), EDC (360 mg, 1.88 mmol), DMAP (58 mg, 0.46 mmol) and (R)-borneol L36-1 (146 mg, 0.94 mmol) in anhydrous dichloromethane (12 mL) was stirred at room temperature for 4h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (SiO 2 : ethyl acetate/hexane 0-20%) to afford L43-2 (220 mg, 75%) as colorless oil. 1 H-NMR (300 MHz, CDCl 3 ) δ 4.89–4.85 (m, 1H), 4.07 (t, 2H), 2.33–2.25 (q, 5H), 2.20–2.05 (m, 2H), 1.68–1.57 (m, 9H), 1.40–1.18 (m, 38 H), 0.88 (m, 12H), 0.81 (s, 3H). Synthesis of 1-(3-pentyloctyl) 17-(1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) 9- hydroxyheptadecanedioate (L43-3): [1092] To a mixture of L43-2 (220 mg, 0.34 mmol) in anhydrous THF (4 mL) and anhydrous MeOH (4 mL) was added sodium borohydride (17 mg, 0.44 mmol) at 0°C. The resulting mixture was then stirred at room temperature for 2h. The reaction was quenched with HCl (1 M), and all the volatile components were reduced under vacuum. The residue was dissolved in diethyl ether and washed with H 2 O and brine. The organic phase was dried over Na 2 SO 4 and reduced under vacuum to obtain crude material which was purified by silica gel column chromatography (ethyl acetate/hexane 0-20%) to get Compound L43-3 (135 mg, 61%) as colorless oil. 1 H-NMR (300 MHz, CDCl 3 ) δ 4.89–4.85 (m, 1H), 4.07 (t, 2H), 3.55 (s, 1H), 2.33–2.25 (m, 4H), 1.65–1.52 (m, 4H), 1.41–1.18 (m, 38 H), 0.88 (m, 11H), 0.82 (s, 3H). Synthesis of 1-(3-pentyloctyl) 17-(1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate (Compound 62): [1093] A mixture of dimethylamino butanoic acid (36 mg, 0.22 mmol), EDC (138 mg, 0.73 mmol) and DMAP (22 mg, 0.18 mmol) in anhydrous dichloromethane (5 mL) was stirred at room temperature for 10 min. A solution of L43-3 (135 mg, 0.18 mmol) in anhydrous dichloromethane (5 mL) was added and the resultant mixture was stirred at room temperature for 4h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (the flash column was equilibrated with 10% triethylamine in hexane before use, eluent: ethyl acetate/hexane 0-50%) to give Compound 62 (120 mg, 75%) as colorless oil. 1 H-NMR (300 MHz, CDCl 3 ) δ 4.89–4.85 (m, 2H), 4.07 (t, 2H), 2.32–2.24 (m, 16H), 1.95-1.48 (m, 15H), 1.27–1.08 (m, 35 H), 0.88 (m, 12H), 0.82 (s, 3H); CIMS m/z 748.7 [M+1]; Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R =11.01 min, purity: >99 %; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No. 186005302),mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 11.64 min, purity: 98.14 %. Synthesis of Compound 63 Synthesis of methyl 9-chloro-9-oxononanoate (L41-2) [1094] To a solution of L41-1 (12 g, 59 mmol) in anhydrous DCM (40 mL) was added anhydrous DMF (1 mL). With ice bath cooling, a solution of oxalyl chloride (8.2 g, 65 mmol) in anhydrous DCM (10 mL) was dropped in under nitrogen with stirring. The resulting mixture was then stirred at room temperature under nitrogen overnight. The reaction mixture was concentrated and co-evaporated with anhydrous toluene to give L41-2 as colorless oil (11.6 g, 97%). 1 H-NMR (300 MHz, CDCl 3 ) δ 3.63 (s, 3H), 2.85 (t, J = 7.2 Hz, 2H), 2.27 (t, J = 7.5 Hz, 2H), 1.77-1.48 (m, 4H), 1.41-1.19 (m, 6H). Synthesis of 9-oxoheptadecanedioic acid (L41-3) [1095] To an ice bath cooled solution of L41-2 (11 g, 50 mmol) in anhydrous toluene (85 mL) was added triethylamine (5g, 50 mmol) in 10 min with stirring while keeping the reaction temperature below 25 °C. After addition finished, the reaction mixture temperature was brought to 35-40 °C during 15-20 min with a warm water bath. After the temperature reached to 40 °C, the water bath was removed, and the reaction mixture was stirred for 1h. It was then filtered through a short pad of celite and the celite cake was rinsed with toluene (25 mL). The combined filtrates were reduced under vacuum to give an oil residue which was mixed with 2N aq. KOH (42 mL). The mixture was refluxed for 6h and then cooled in ice-bath. The aqueous layer was washed with ether (35 mL x 3) and acidified with concentrated HCl to pH 4. After cooling the mixture in ice bath for 1h, the precipitates were filtered, washed with ice cold water and dried to yield L41-3 as an off-white solid (6.0 g, 71%). 1 H-NMR (300 MHz, DMSO-d 6 ) δ 2.38 (t, J = 7.1 Hz, 4H), 2.18 (t, J = 7.4 Hz, 4H), 1.53-1.35 (m, 8H), 1.33-1.02 (m, 12H). Synthesis of bis((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) 9-oxohepta decanedioate (L41-4) [1096] To a solution of L41-3 (950 mg, 1 eq) and L36-1 (978mg, 2.1 eq) in dichloromethane (19 mL) was added EDC (2.3 g, 4 eq) and DMAP (369 mg, 1 eq). The reaction mixture was stirred under nitrogen for 31 hours until TLC (20% EA in hexane, R f =0.9) showed completion of the reaction. Solvent was removed under vacuum to obtain crude material which was purified by silica gel column chromatography using 0 – 40% EA in hexane as eluent to afford L41-4 (1.03 g, 57%). 1 H-NMR (300 MHz, CDCl3) δ 4.86 (tt, 2H), 2.42-2.24 (m, 10H), 1.98- 1.84 (m, 2H), 1.82-1.46 (m, 12H), 1.38-1.14 (m, 16H), 0.89 (s, 6H), 0.87 (s, 6H), 0.81 (s, 6H); CIMS m/z [M+H] + 587.5. Synthesis of ethyl bis((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) 9-hydroxyhepta decanedioate (L41-5) [1097] To a solution of L41-4 (1.03 g, 1 eq) in THF (6 mL) and methanol (3 mL) was added sodium borohydride (70.8 mg, 1 eq) at room temperature. The reaction mixture was stirred under nitrogen atmosphere until TLC (20% EA in hexane, R f =0.5) showed completion of the reaction. The reaction was quenched with HCl (1 M), and all the volatile components were reduced under vacuum. The residue was dissolved in diethyl ether and washed with H 2 O and brine. The organic phase was dried over Na 2 SO 4 and reduced under vacuum to obtain crude material which was purified by silica gel column using 0 – 50% EA in hexane as eluent to yield L41-5 (825 mg, 80%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.86 (tt, 2H), 3.55 (bs, 1H), 2.42-2.24 (m, 10H), 1.98-1.84 (m, 2H), 1.82-1.46 (m, 12H), 1.38-1.14 (m, 16H), 0.89 (s, 6H), 0.87 (s, 6H), 0.81 (s, 6H); CIMS m/z [M+H] + 589.5. Synthesis of bis((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate (Compound 63) [1098] To a solution of L41-2 (825 mg, 1 eq), 4-(dimethylamino)butanoic acid (304 mg, 1.2 eq), 4-dimethylaminopyridine (34 mg, 0.2 eq) and N, N-diisopropylethylamine (0.5 mL, 2 eq) in DCM (7.5 mL) was added EDC (358 mg, 1.33 eq). The mixture was purged with nitrogen and stirred for 16 hours. The reaction was diluted with DCM, washed with aq. NaHCO 3 and brine. The organic phase was dried over Na 2 SO 4 and reduced under vacuum to obtain crude product which was purified by silica column chromatography using 0 – 10% MeOH in DCM as eluent to afford Compound 63 (0.87 g, 89%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.86 (m, 3H), 2.38-2.22 (m, 10H), 2.21 (s, 6H), 1.96-1.89 (m, 2H), 1.80-1.70 (m, 4H), 1.67 (t, 2H), 1.63-1.58 (m, 4H), 1.50-1.48 (m, 4H), 1.32-1.18 (m, 20H), 0.96 (d, 1H), 0.93 (d, 1H), 0.90 (s, 6H), 0.87 (s, 6H), 0.81 (s, 6H); CIMS m/z [M+H] + 702.5. Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 5.82 min, purity: >99.9%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No. 186005302),mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 20 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 8.75 min, purity: >99.9%. Synthesis of Compound 64 Synthesis of bis((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) 9- oxoheptadecanedioate (L42-1) [1099] To a solution of L41-3 (1.0 g, 1 eq) and L37-1 (1.03 g, 2.1 eq) in dichloromethane (20 mL) was added EDC (2.44 g, 4 eq) and 4-dimethylaminopyridine (3.88 g, 1 eq). The reaction mixture was stirred under N 2 for 31 hours until TLC (20% EA in hexane, R f = 0.9) showed completion of the reaction. Solvent was removed under vacuum to obtain crude material which was then purified by silica gel column using 0 –70% EA in hexane as eluent to afford L42-1 (1.51g, 80%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.86 (tt, 2H), 2.42-2.24 (m, 10H), 1.98-1.84 (m, 2H), 1.82-1.46 (m, 12H), 1.38-1.14 (m, 16H), 0.89 (s, 6H), 0.87 (s, 6H), 0.81 (s, 6H); CIMS m/z [M+H] + 587.5. Synthesis of bis((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) 9- hydroxyheptadecanedioate (L42-2) [1100] To a solution of L42-1 (1.51 g, 1 eq) in THF (9 mL) and methanol (4.5 mL) was added sodium borohydride (103 mg, 1 eq). The reaction mixture was stirred under nitrogen atmosphere for 16 hours. The reaction was quenched with HCl (1 M), and all the volatile components were reduced under vacuum. The residue was dissolved in diethyl ether and washed with H 2 O and brine. The organic phase was dried over Na 2 SO 4 and reduced under vacuum to obtain crude material which was purified by silica gel column using 0 – 50% EA in hexane as eluent to yield L42-2 (1.09 g, 72%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.86 (tt, 2H), 3.55 (bs, 1H), 2.42-2.24 (m, 10H), 1.98-1.84 (m, 2H), 1.82-1.46 (m, 12H), 1.38-1.14 (m, 16H), 0.89 (s, 6H), 0.87 (s, 6H), 0.81 (s, 6H); CIMS m/z [M+H] + 589.5. Synthesis of bis((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) 9-((4- (dimethylamino)butanoyl)oxy)heptadecanedioate (Compound 64) [1101] To a mixture of L42-2 (1090 mg, 1 eq), 4-(dimethylamino)butanoic acid (402 mg, 1.3 eq), 4-dimethylaminopyridine (45 mg, 0.2 eq), N, N-diisopropylethylamine (0.64 mL, 2 eq) in DCM (10 mL) was added EDC (473 mg, 1.33 eq). The mixture was purged with nitrogen and stirred for 16 hours. The reaction mixture was then diluted with DCM and washed with NaHCO 3 and brine. The organic phase was dried over Na 2 SO 4 and reduced under vacuum to obtain crude product which was purified by silica gel using 0 – 90% EA with 1% triethylamine in hexane as eluent to yield Compound 64 (0.773 g, 59%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.86 (m, 3H), 2.38-2.22 (m, 10H), 2.21 (s, 6H), 1.96-1.89 (m, 2H), 1.80-1.70 (m, 4H), 1.67 (t, 2H), 1.63-1.58 (m, 4H), 1.50-1.48 (m, 4H), 1.32-1.18 (m, 20H), 0.96 (d, 1H), 0.93 (d, 1H), 0.90 (s, 6H), 0.87 (s, 6H), 0.81 (s, 6H); CIMS m/z [M+H] + 702.5. Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 5.94 min, purity: >99.9%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No.186005302),mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 20 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 8.71 min, purity: >99.9%. Synthesis of Compound 65 Synthesis of 1-((3S,10R,13R,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2- yl)-2,3,4,7,8,9, 10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phena nthren-3-yl) 17-(3- pentyloctyl)-9-oxoheptadecanedioate (L45-1): [1102] A mixture of L43-1 (300 mg, 0.604 mmol), EDC (467.07 mg, 2.415 mmol), DMAP (74 mg, 0.604 mmol) and cholesterol (466.99 mg, 1.207 mmol) in anhydrous dichloromethane (30 mL) was stirred at room temperature for 2h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (SiO 2 : ethyl acetate/hexane 0-20%) to afford Compound L45-1 (301 mg, 29%) as slightly yellow oil. 1 H NMR (300 MHz, CDCl 3 ): δ ppm 5.35 (d, J =5.0 Hz, 1H), 4.70-4.55 (m, 1H), 4.07 (t, J =6.0 Hz, 2H), 2.43-2.20 (m, 12H), 2.10-1.79 (m, 6H), 1.73-0.81 (m, 75H), 0.67 (s, 3H); MS (CI): m/z [M+H] + 866.44. Synthesis of 1-((3S,10R,13R,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2- yl)-2,3,4,7,8,9, 10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phena nthren-3-yl) 17-(3- pentyloctyl) 9-hydroxyheptadecanedioate (L45-2): To a mixture of L45-1 (300 mg, 0.604 mmol) in anhydrous THF (10mL) and anhydrous MeOH (10mL) was added sodium borohydride (30 mg, 0.785 mmol) at 0°C. The resulting mixture was then stirred at room temperature for 2h. The reaction was quenched with HCl (1 M), and the volatile components were reduced under vacuum. The residue was dissolved in diethyl ether and washed with H 2 O and brine. The organic phase was dried over Na 2 SO 4 and reduced under vacuum to obtain crude material which was purified by silica gel column chromatography (ethyl acetate/hexane 0-20%) to get Compound L45-2 (290 mg, 96%) as slightly yellow oil. 1 H NMR (300 MHz, CDCl 3 ): δ ppm 5.35 (d, J =5.0 Hz, 1H), 4.68-4.54 (m, 1H), 4.07 (t, J =6.0 Hz, 2H), 3.56(s, 1H), 2.35-2.20 (m, 6H), 2.06-1.76 (m, 6H), 1.71-0.81 (m, 82H), 0.66 (s, 3H); MS (CI): m/z [M+H] + 868.44. Synthesis of 1-((3S,10R,13R,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2- yl)-2,3,4,7,8,9, 10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phena nthren-3-yl) 17-(3- pentyloctyl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (Compound 65): [1103] A mixture of dimethylamino butanoic acid (65 mg, 0.387 mmol), EDC (2.475 g, 1.29 mmol), and DMAP (39.5 mg, 0.322 mmol) in anhydrous dichloromethane (30mL) was stirred at room temperature for 10 min. A solution of L45-2 (280 mg, 0.322 mmol) in anhydrous dichloromethane (5 mL) was added and the resultant mixture was stirred at room temperature for 4h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (the flash column was equilibrated with 10% triethylamine in hexane before use, eluent: ethyl acetate/hexane 0-50%) to give Compound 65 (200 mg, 53%). 1 H NMR (300 MHz, CDCl 3 ): δ 5.45 (d, J =5.0 Hz, 1H), 4.88-4.68 (m, 1H), 4.67-4.58 (m, 1H), 4.08 (t, J =6.0 Hz, 2H), 2.33-2.1 (m, 20H), 2.10-1.92 (m, 2H), 1.96-1.76 (m, 7H), 1.62-1.12 (m, 37H), 1.10-0.87 (m, 5H), 0.86-0.83 (m, 14H), 0.66 (s, 3H); MS (CI): m/z [M+H] + 980.60. Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mmol, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 10.7 min, purity: >98.3%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No.186005302),mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 13.1 min, purity: >99%. Synthesis of Compound 66 Synthesis of 1-(2-(bicyclo[2.2.2]octan-1-yl)ethyl) 17-(3-pentyloctyl) 9-oxohepta- decanedioate (L48-2): [1104] A mixture of L43-1 (532 mg, 1.07 mmol), EDC (746 mg, 3.88 mmol), DMAP (119 mg, 0.97 mmol) and L48-1 (150 mg, 0.97 mmol) in anhydrous dichloromethane (10mL) was stirred at room temperature for 4h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (SiO 2 : ethyl acetate/hexane 0-20%) to afford Compound L48-2 (530 mg, 73%) as slightly yellow oil. 1 H NMR (300 MHz, CDCl 3 ): δ ppm 4.19-4.02 (m, 4H), 2.41-2.21 (m, 8H), 1.82-1.20 (m, 54H), 0.87 (t, J =7.0 Hz, 6H). MS (CI): m/z [M+H] + 634.2 Synthesis of 1-(2-(bicyclo[2.2.2]octan-1-yl)ethyl) 17-(3-pentyloctyl) 9-hydroxyhepta decanedioate (L48-3): [1105] To a mixture of L48-2 (520 mg,0.821 mmol) in anhydrous THF (10mL) and anhydrous MeOH (10mL) was added sodium borohydride (41 mg, 1.1 mmol) at 0°C. The resulting mixture was then stirred at room temperature for 2h. The reaction was quenched with HCl (1 M), and all the volatile components were reduced under vacuum. The residue was dissolved in diethyl ether and washed with H 2 O and brine. The organic phase was dried over Na 2 SO 4 and reduced under vacuum to obtain crude material which was purified by silica gel column (ethyl acetate/hexane 0-20%) to get Compound L48-3 (450 mg, 86%) as slightly yellow oil. 1 H NMR (300 MHz, CDCl 3 ): δ ppm 4.19-4.03 (m, 4H), 3.71-3.60 (m, 1H), 2.36-2.21 (m, 4H), 1.82-1.39 (m, 14H), 1.38-1.22 (m, 44H), 0.87 (t, J =7.0 Hz, 6H). MS (CI): m/z [M+H] + 636.28. Synthesis of 1-(2-(bicyclo[2.2.2]octan-1-yl)ethyl) 17-(3-pentyloctyl) 9-((4-(dimethylamino) butanoyl)oxy)heptadecanedioate (66): [1106] A mixture of dimethylamino butanoic acid (164.05 mg, 0.98 mmol), EDC (536.13 mg, 2.79 mmol), and DMAP (93.96 mg, 0.77 mmol) in anhydrous dichloromethane (10mL) was stirred at room temperature for 10 min. A solution of L48-3 (444 mg, 0.69 mmol) in anhydrous dichloromethane (5 mL) was added and the resultant mixture was stirred at room temperature for 4h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (the flash column was equilibrated with 10% triethylamine in hexane before use, eluent: ethyl acetate/hexane 0-50%) to give Compound 66 (450 mg, 8 6%).1 H NMR (300 MHz, CDCl3): δ ppm 4.86 (t, J =7.0 Hz, 1H), 4.07-4.0 (m, 4H), 2.32-2.20 (m, 14H), 1.86-1.73 (m, 1H), 1.63-1.44 (m, 18H), 1.43-1.19 (m, 41H), 0.87 (t, J =7.0 Hz, 6H); MS (CI): m/z [M+H] + 749.20. Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mmol, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 10.7 min, purity: 87.94%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No.186005302),mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 13.1 min, purity: >99%. Synthesis of Compound 67 Synthesis of (1R,5S,6S)-bicyclo[3.2.1]octane-6-yl 8 Bromo octanoate (L35-2) [1107] To a solution of L1-5 (2.28 g, 10.30 mmol, 1.3 eq) and L35-1 (1.0 g,7.93 mmol, 1.0 eq) in DCM (15 ml) was added EDC (4.5 g, 23.79mmol, 3.0 eq) and DMAP (0.484 g, 4.0 mmol, 0.5 eq). The reaction was stirred at room temperature for 3 h and reduced under vacuum to dryness. The crude was purified by column (10% Ethyl acetate/hexane) to give L35-2 as colorless oil (1.4 g, 53%). 1 HNMR (CDCl 3 ) δ 4.94-4.96 (dd, 1H), 3.36-3.51 (t, 2H), 2.21-2.26 (m, 3H), 1.95-2.15 (m, 2H), 1.45-1.60 (m, 4H), 1.28-1.36(m, 7H); CIMS m/z [M+H] + 331. Synthesis of (1R,5S,6S)-bicyclo [3.2.1] octan-6-yl 8-((4-hydroxybutyl) (8-oxo-8-((3- pentyloctyl) oxy) octyl) amino) octanoate (Compound 67) [1108] To a solution of L32-1 (480 mg, 1.2 mmol, 1.0 eq) and L35-2 (500 mg, 1.5 mmol, 1.3 eq) in a 1:1 mixture of ACN (12 ml) and CPME (12ml) was added K 2 CO 3 (oven dried: 497 mg , 3.6 mmol, 3.0 eq) and KI (100 mg, 0.6 mmol, 0.5 eq). The reaction mixture was heated at 80° C for 22 h. After cooling to room temperature, the reaction mixture was filtered through celite. The celite cake was washed with ACN (50 ml), The combined filtrates were concentrated and purified by column (1 to 100% EA in Hexane) to give Compound 67 as colorless oil (370 mg, 47%). 1 HNMR (CDCl 3 ) δ: 6.70 (bs,1H), 4.9 (dd, 1H), 4.04-4.09 (t, 2H), 5.01-5.03 (bs, 2H), 2.38-2.43 (m, 5H), 2.23-2.27 (m, 5H), 1.95-2.15 (m, 5H), 1.57 – 1.64 (m, 16H), 1.30-1.40 (m, 41H) 0.85 – 0.87 (t, 6H); CIMS m/z [M+H] + 664.1; Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 7.78 min, purity: > 99%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No.186005302),mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 8.42 min, purity: 97.5%.
Synthesis of Compound 68 Synthesis of 3-pentyloctyl 8-((2-hydroxyethyl)(8-oxo-8-(((1S,2R,4S)-1,7,7-trimethyl- bicyclo[2.2.1]heptan-2-yl)oxy)octyl)amino)octanoate (L72-1) [1109] To a mixture of 3-pentyloctyl 8-((2-hydroxyethyl)amino)octanoate L31-1 (446 mg, 1.08 mmol) and L37-2 (446 mg, 1.08 mmol) in a mixture of AcCN/CPME (1:1, 10 mL) under nitrogen was added K 2 CO 3 (447 mg, 3.24 mmol) followed by KI (90 mg, 0.54 mmol). The reaction mixture was heated at 80°C for overnight under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered through celite, celite cake was washed with acetonitrile. The filtrate was concentrated to give crude product, which was purified by flash chromatography (SiO 2 : 0 to 10% MeOH in DCM (1% NH 4 OH) gradient) to yield L72-1 as colorless oil (505 mg, 68%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.89-4.85 (m, 1H), 4.07 (t, J = 7.0 Hz, 2H), 3.51 (t, J = 5.3 Hz, 2H), 2.62-2.21 (m, 10H), 1.99-1.15 (m, 44H), 1.03-0.86 (m, 18H); CIMS m/z [M+H] + 664.3. Synthesis of heptadecan-9-yl 2-(1-(4-(benzyloxy)butyl)-4-(2-oxo-2-((3- pentyloctyl)oxy)ethyl)piperidin-4-yl)acetate (68) [1110] To a solution of L72-1 (320 mg, 0.58 mmol) in DCM (10 mL) was added thiazole-4- carboxylic acid L72-2 (225 mg, 0.88 mmol) followed by DMAP (38 mg, 0.3 mmol) and EDC (225 mg, 1.2 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 18 h. The reaction mixture was diluted with DCM (15 mL) and washed with brine (10 mL). The organic phase was dried over anhydrous Na 2 SO 4 . Filtration and concentration provided crude material which was purified by flash column chromatography (SiO 2 : ethyl acetate/hexane 0-100%) to yield Compound 68 as colorless oil (305 mg, 66%). 1H-NMR (300 MHz, CDCl 3 ) δ 8.85 (d, J = 2.2 Hz, 1H), 8.24 (s, 1H), 4.89-4.85 (m, 1H), 4.09 (t, J = 6.6 Hz, 2H), 4.07 (t, J = 7.1 Hz, 2H), 2.84 (t, J = 5.8 Hz, 2H), 2.48 (t, J = 6.3 Hz, 4H), 2.39-2.21 (m, 4H), 1.99-1.15 (m, 43H), 1.03-0.86 (m, 18H); CIMS m/z [M+H] + 775.1; Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 6.7 min, purity: > 99%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No.186005302), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 60% to 100% in 15 min, flow rate: 0.5mL/min, column temperature: 20±2 °C, detector: CAD, t R = 10.7 min, purity: > 99%. Synthesis of Compound 69 Synthesis of 2-(bicyclo[2.2.2]octan-1-yl)ethyl 8-((4-hydroxybutyl)(8-oxo-8-((3- pentyloctyl)oxy)octyl)amino)octanoate (Compound 69) [1111] The starting material L32-1 (383 mg, 1 eq), K 2 CO 3 (512 mg, 4 eq), and KI (154 mg, 1 eq) were mixed with CH 3 CN/CPME (2/2 mL). After adding L71-2 (400 mg, 1.2 eq) to the above solution, the reaction mixture was stirred for 68 hours at 95 °C. The reaction mixture was then filtered through filter paper The organic fraction was reduced under vacuum to obtain crude product which was then subjected to silica gel column using 0 – 10% MeOH in DCM with 1% NH 3 •H 2 O as eluent to afford Compound 69 as light-yellow oil (403 mg, 63%). 1 H- NMR (300 MHz, CDCl 3 ) δ 4.05 (tt, 4H), 3.61 (m, 2H), 2.67 (bs, 6H), 2.26 (tt, 4H), 1.85-1.42 (m, 26H), 1.41-1.10 (m, 32H), 0.87 (t, 6H). CIMS m/z [M+H] + 692.1. Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 5 min, then 100% for 10 min. Flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 5.72 min, purity: 99.8%; UPLC column: Thermo Scientific Hypersil GOLD C18, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 5 min, then 100% for 15 min. Flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 10.82 min, purity: 95.0%. Synthesis of Compound 70 Synthesis of 4-(thiazol-2-yl)but-3-yn-1-ol (L73-2) [1112] 2-Bromothiazole (2 g, 12.18 mmol) was dissolved in triethylamine (50 mL) under nitrogen atmosphere. CuI (70 mg, 0.36 mmol), Pd(PPh 3 ) 4 (281.5 mg, 0.24 mmol) and but-3- yn-1-ol (1.28 g, 18.2 mmol) were added and the solution was heated to reflux for 18 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (SiO 2 : Hexane/ EtOAc` 0-100%) to get Compound L73-2 (1.44 g, 77%) as orange oil. 1 H-NMR (300 MHz, CDCl 3 ) δ 7.76 (d, 1H), 7.28 (d, 1H), 3.87 (t, 2H), 2.76 (t, 2H); APCI-MS: m/z [M+H] + 154. Synthesis of 4-(thiazol-2-yl)butan-1-ol (L73-3) [1113] To a solution of L73-2 (1.44 g, 9.35 mmol) in methanol (10 mL) was added 10% Pd/C (100 mg) at room temperature and the mixture was subjected to parr-shaker hydrogenator under hydrogen atmosphere (40 psi) for 18 h. Upon completion, the mixture was filtered through a celite pad and concentrated under reduced pressure and the crude was purified by column chromatography (SiO 2 : DCM/DCM:MeOH (9:1)) to get Compound L73-3 (1.22 g, 76%) as orange oil. 1 H-NMR (300 MHz, CDCl 3 ) δ 7.66 (d, 1H), 7.19 (d, 1H), 3.68-3.64 (m, 2H), 3.09- 3.04 (m, 2H), 1.90-1.81 (m, 2H), 1.69-1.66 (m, 2H); APCI-MS: m/z [M+H] + 158. Synthesis of 4-(thiazol-2-yl)butanal (L73-4) [1114] To an ice bath cooled solution of L73-3 (0.61 g, 3.88 mmol) in anhydrous DCM (15 mL) under nitrogen were added Dess–Martin periodinane (1.97 g, 4.65 mmol) in portion. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched by slow addition of saturated Na 2 SO 3 (2 mL) and NaHCO 3 (2 mL) and stirred for a few minutes then acetic acid (1 mL) were added. The reaction mixture were concentrated under reduced pressure to dryness and the crude was purified by column chromatography (SiO 2 : DCM/ DCM:MeOH (9:1)) to get Compound L73-4 (0.3 g, 50%) as light yellow oil. 1 H-NMR (300 MHz, CDCl 3 ) δ 9.76 (s, 1H), 7.66 (d, 1H), 7.19 (d, 1H), 3.06 (t, 2H), 2.56 (t, 2H), 2.15 (t, 2H); APCI-MS: m/z [M+H] + 156. Synthesis of 3-pentyloctyl 8-(benzylamino)octanoate (L71-5) [1115] To 100 mL round bottom flask containing L1-6 (1.0 g, 2.46 mmol) and benzylamine (3.61 g, 33.68 mmol) was added ethanol (10 mL). The reaction mixture was subjected to vacuum/N 2 cycle (3x) and stirred under nitrogen at 70 °C for 24 h. The solvent was removed under vacuum to dryness and purified by flash chromatography (SiO 2 : hexane /ethyl acetate 0- 55%) to get Compound L71-5 (890 mg, 84%) as yellow oil. 1 H-NMR (300 MHz, CDCl 3 ) δ 7.32-7.25 (m, 5H), 4.09 (t, 2H), 3.77 (s, 2H), 2.63 (t, 2H), 2.27 (t, 2H), 1.57-1.24 (m, 29H), 0.87 (t, 6H); APCI-MS: m/z [M+H] + 432.2. Synthesis of 3-pentyloctyl 8-(benzyl(8-oxo-8-(((1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1] heptan-2-yl)oxy)octyl)amino)octanoate (L73-5) [1116] To a 100 mL round bottom flask containing L71-5 (0.88 g, 2.03 mmol), L37-2 (0.80 g, 2.24 mmol), K 2 CO 3 (0.84 g, 6.09 mmol), KI (0.50 g, 3.04 mmol) was added anhydrous acetonitrile (5 mL) along with cyclopentylmethyl ether (CPME) (5 mL) and the reaction mixture was stirred under reflux at 90 °C for 48 h. After completion of the reaction the solvent was removed under vacuum and purified by flash chromatography (SiO 2 : hexane (1% TEA)/ ethyl acetate (0-100%)) to get Compound L73-5 (1.37 g, 95%) as colorless oil. 1 H-NMR (300 MHz, CDCl 3 ) δ 7.30-7.25 (m, 5H), 4.90 (dd, 1H), 4.09 (t, 2H), 3.51 (s, 2H), 2.36-2.26 (m, 8H), 2.0-1.85 (m, 1H), 1.85-1.10 (m, 46H), 0.89-0.81 (m, 15H); APCI-MS: m/z [M+H] + 710.3. Synthesis of 3-pentyloctyl 8-((8-oxo-8-(((1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan -2- yl)oxy)octyl)amino)octanoate (L73-6) [1117] To 100 mL round bottom flask containing L73-5 (1.37 g, 1.92 mmol) and 20% Pd(OH) 2 /C (600 mg) was added methanol (10 mL). The reaction mixture was subjected to vacuum/N 2 cycle (3x) followed by another cycle of vacuum/H 2 (3x). The hydrogen balloon was placed on the top of septum and left stirring for 4 days. Another 20% Pd(OH) 2 /C (300 mg) was added and the reaction mixture was subjected to parr-shaker hydrogenator under hydrogen atmosphere (40 psi) for 18 h. The reaction mixture diluted with ethyl acetate (100 mL) and then filtered through Celite, washed with ethyl acetate and methanol. The solvent was removed under vacuum to dryness and used to the next step without further purification (SiO 2 : hexane (10% triethyl amine)/ethyl acetate 0-38%) to get Compound L73-6 (1.15 g, 97%) as light-yellow oil. 1 H-NMR (300 MHz, CDCl3) δ 4.90 (dd, 1H), 4.09 (t, 2H), 3.51 (s, 2H), 2.36- 2.26 (m, 8H), 2.0-1.85 (m, 1H), 1.85-1.10 (m, 46H), 0.89-0.81 (m, 15H); APCI-MS: m/z [M+H] + 620.3. Synthesis of 3-pentyloctyl 8-((8-oxo-8-(((1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan -2- yl)oxy)octyl)(4-(thiazol-2-yl)butyl)amino)octanoate (Compound 70) [1118] To the mixture of L73-6 (599.16 mg, 0.96 mmol) and L73-4 (300 mg, 1.93 mmol) in 1,2-Dichloroethane (15 mL) was added Na(OAc) 3 BH (610.38 mg, 2.88 mmol) and acetic acid (0.05 mL, 0.96 mmol). The reaction mixture was subjected to vacuum/N 2 cycle (3x) and stirred under nitrogen at room temperature for 18 h. The reaction was quenched by slow addition of saturated NaHCO 3 (100 mL) at 0 °C. The aqueous phase was extracted using DCM (100 mL, 3x) and the combined organic phases were dried over anhydrous Na 2 SO 4 . Filtration followed by concentration provided crude material which was loaded on 20 g flash silica column and was purified by flash chromatography (SiO 2 : hexane/ ethyl acetate (0 to 100%)) followed by another column using (DCM: MeOH: NH 4 OH (9:1:0.1)) to yield Compound 70 (235 mg, 32%) as slightly yellow oil. 1 H-NMR (300 MHz, CDCl 3 ) δ 7.31-7.30 (m, 5H), 4.46 (s, 2H), 4.09- 4.04 (m, 4H), 3.47-3.43 (m, 2H), 2.52-2.31 (m, 10H), 1.68-1.57(m, 8H), 1.22 (t, 6H); APCI- MS: m/z [M+H] + 420.3; Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 11.6 min, purity: >99 %; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No. 186005302),mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 13.8 min, purity: >99%. Synthesis of Compound 71 Synthesis of 3-pentyloctyl 8-(prop-2-yn-1-ylamino)octanoate (L71-1): [1119] A solution of L1-6 (1.0 g, 2.46 mM) and propargyl amine (1.36 g, 24.66 mM) in ethanol (40 mL) was refluxed for 18 h. After completion of the reaction, the solvent was removed under vacuum. Residual paste was purified by flash chromatography (SiO 2 : ethyl acetate/hexane 0- 100%) to get L71-1 (520 mg, 55%) as colorless oil. 1 H NMR (300 MHz, CDCl 3 ): δ ppm: 4.07 (t, J = 7.0 Hz, 2H), 3.41 (d, J = 2.0 Hz, 2H), 2.67 (t, J = 7.0 Hz, 2H), 2.27 (t, J = 7.0 Hz, 2H), 2.20 (t, J =2.0 Hz, 1H), 1.61-1.22 (m, 30H), 0.87 (t, J = 7.5 Hz, 6H). MS (CI): m/z [M+H] + 380.42. Synthesis of 2-(bicyclo[2.2.2]octan-1-yl)ethyl 8-bromooctanoate (L71-2): [1120] To a 100 mL round bottom flask L1-5 (600 mg, 3.38 mM), EDC (1.49 g, 7.78 mM), were added in anhydrous dichloromethane (20 mL) and the reaction mixture was stirred for 15 min. To this was added DMAP (478.2 mg, 3.89 mM) and L48-1 (600 mg, 3.38 mM) in anhydrous dichloromethane (5 mL). The resulting mixture was stirred under nitrogen at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (SiO 2 : ethyl acetate/hexane 0-20%) to get L71- 2 (910 mg, 65%) as a clear oil. 1 H NMR (300 MHz, CDCl 3 ): δ ppm: 4.06 (t, J = 7.0 Hz, 2H), 3.39 (d, J = 2.0 Hz, 2H), 2.26 (t, J = 7.0 Hz, 2H), 1.91-1.72 (m, 2H), 1.71-1.31 (m, 23H). MS (CI): m/z [M+H] + 360.43. Synthesis of 2-(bicyclo[2.2.2]octan-1-yl)ethyl 8-((8-oxo-8-((3-pentyloctyl)oxy)octyl)(prop-2- yn-1-yl)amino)octanoate (L71-3): [1121] A mixture of L71-1 (420 mg, 1.10 mM), L71-2 (477 mg, 1.33 mM), KI (275.5 mg, 1.65 mM) and potassium carbonate (458.7 mg, 3.32 mM) in anhydrous ACN (2.5 mL) and cyclopentylmethyl ether (CPME) (2.5 mL) was refluxed under nitrogen at 120 °C for 24 h. After cooling to room temperature, the reaction mixture was filtered through celite and the celite cake was washed with acetonitrile. The filtrate was concentrated to give crude product, which was purified by flash chromatography (the flash column was equilibrated with 10% triethylamine in hexane before use, eluent: ethyl acetate/hexane 0-50%) to get Compound L71- 3 (410 mg, 56%). 1 H NMR (300 MHz, CDCl 3 ): δ ppm: 4.17-4.02 (m, 4H), 3.39 (d, J = 2.0 Hz, 2H), 2.43 (t, J = 7.0 Hz, 4H), 2.30 (t, J = 7.0 Hz, 4H), 2.15 (s, 1H), 1.61-1.22 (m, 54H), 0.87 (t, J = 7.5 Hz, 6H). MS (CI): m/z [M+H] + 658.08. Synthesis of 2-(bicyclo[2.2.2]octan-1-yl)ethyl 8-((8-oxo-8-((3-pentyloctyl)oxy)octyl)(3- (thiazol-2-yl)prop-2-yn-1-yl)amino)octanoate (L71-5): [1122] A mixture of L71-3 (235 mg, 0.357 mM), L71-4 (87.8 mg, 0.535 mM), Pd(PPh 3 ) 4 (41.2 mg, 0.03 mM) and copper iodide (13.6 mg, 0.07 mM) in triethylamine (5 mL) was refluxed under nitrogen for 18 h. Solvent was removed under vacuum and the residue was purified by flash chromatography (SiO 2 : ethyl acetate/hexane 0-50%) to get L71-5 (146 mg, 55%). 1 H NMR (300 MHz, CDCl 3 ): δ ppm: 7.77 (d, J = 7.0 Hz, 1H), 7.31 (d, J = 7.0 Hz, 1H), 4.16-4.02 (m, 4H), 3.65 (s, 2H), 2.47 (t, J = 8.0 Hz, 4H), 2.25 (t, J = 8.0 Hz, 4H), 1.58-1.22 (m, 54H), 0.87 (t, J = 7.5 Hz, 6H). MS (CI): m/z [M+H] + 741.18. Synthesis of 2-(bicyclo[2.2.2]octan-1-yl)ethyl 8-((8-oxo-8-((3-pentyloctyl)oxy)octyl)(3- (thiazol-2-yl)propyl)amino)octanoate (Compound 71): [1123] A mixture of L71-5 (182 mg, 0.245 mM), and Palladium (II) hydroxide (103.5 mg, 0.3 eq) in ethyl acetate (5 mL) was stirred under 1 atm hydrogen (balloon) at room temperature for 3 days. After completion of the reaction, the reaction flask was degassed, and the palladium was filtered using celite pad. The filtrate was concentrated under vacuum and the residue was purified by flash chromatography (SiO 2: ethyl acetate/hexane 0-50%) to get Compound 71 (40 mg, 22%). 1 H NMR (300 MHz, CDCl 3 ): δ ppm: 7.78 (d, J = 7.0 Hz, 1H), 7.25 (d, J = 7.0 Hz, 1H), 4.16-4.03 (m, 4H), 3.15-3.01 (m, 2H), 2.42-2.25 (m, 10H), 2.05-1.90 (m, 2H), 1.61-1.24 (m, 54H), 0.87 (t, J = 7.5 Hz, 6H). MS (CI): m/z [M+H] + 745.28. Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 8.2 min, purity: 95.95%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No.186005302), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 60% to 100% in 15 min, flow rate: 0.5mL/min, column temperature: 20±2 °C, detector: CAD, t R = 11.56 min, purity: 87.14%.
Synthesis of Compound 72 Synthesis of dec-9-enal (L83-2) [1124] Starting material L83-1 (5 g, 1 eq) was dissolved in DCM (130 mL) and cooled to 0 °C. The Dess Martin periodinane (15.1 g, 1 eq) was added slowly. The reaction mixture was stirred at 0 °C for 10 minutes then brought to room temperature and stirred for 2 hours. To the reaction mixture was added 1 M NaOH (100 mL) and the organic layer was separated. Aqueous phase was extracted by DCM (100 mL × 2). Combined organic phases were reduced under vacuum to give slightly cloudy crude product which was dissolved in a small amount of DCM and passed through a silica gel column using 0 – 5% EA in hexane as eluent to afford L83-2 as colorless liquid (2.8 g, 57%). 1 H-NMR (300 MHz, CDCl 3 ) δ 9.76 (s, 1H), 5.88-5.62 (m, 1H), 5.05-4.89 (m, 2H), 2.51-2.32 (m, 2H), 2.12-1.90 (m, 2H), 1.71-1.50 (2, 1H), 1.48- 1.13 (m, 8H). Synthesis of 1-((tert-butyldimethylsilyl)oxy)hexadec-15-en-7-ol (L83-4) [1125] Preparation of Grignard reagent: Magnesium turnings (329 mg, 4 eq) were put in a 50 mL round bottom flask and purged with nitrogen for 15 min. THF (3 mL), and 1,2- dibromoethane (58 μL, 0.2 eq) were added in sequence under nitrogen. The reaction was sealed and stirred for 3 min. ((6-bromohexyl)oxy)(tert-butyl)dimethylsilane (1.0 g, 1 eq) was dissolved in THF (10 mL) and dropped into the reaction mixture. The mixture was stirred at room temperature for 1 h and then at 60 °C for another hour. The dark grey solution was then cooled down to room temperature and used immediately. L83-2 (174 g, 1 eq) was added to the above Grignard reagent (~ 1.08 g in 13 mL THF, 3 eq) dropwise over 10 min. The reaction was stirred at room temperature for 2 hours, at which time, TLC (EA/hexane = 1/4, R f = 0.7) showed completion of the reaction. Water (10 mL) was added slowly, and the mixture was extracted with ethyl acetate (EA) (10 mL × 2). The organic layer was dried over Na 2SO4 and reduced under vacuum to obtain crude product. The crude product was dissolved in a small amount of DCM and subjected to silica gel column using 0 – 25% EA in hexane as eluent to afford pure product L83-4 as colorless oil (300 mg, 72%). 1 H-NMR (300 MHz, CDCl 3 ) δ 5.88-5.62 (m, 1H), 5.05-4.89 (m, 2H), 3.67-3.50 (m, 3H), 2.11-1.94 (m, 2H), 1.72-1.13 (m, 27H), 0.90 (s, 9H), 0.04 (s, 6H). CIMS m/z [M+H] + 371.1. Synthesis of 15-((tert-butyldimethylsilyl)oxy)-9-oxopentadecanoic acid (L83-5) [1126] The starting material L83-4 (1.4 g, 1 eq), NaIO 4 (6.4 g, 8 eq), and RuCl 3 (140 mg, 0.1 eq) were dissolved in ACN/CCl 4 /H 2 O (40/40/60 mL) respectively. The three components were combined and the resulting mixture was stirred at room temperature for 20 hours. When TLC (15% MeOH in DCM, R f = 0.4) showed completion of the reaction, H 2 O (100 mL) was added to dilute the reaction and DCM (100 mL × 2) was used to extract crude product. The organic solvent was reduced under vacuum to obtain crude product which was then subjected to silica gel column using 0 – 15% MeOH in DCM as eluent to afford L83-5 as light yellow oil (663 mg, 46%). 1 H-NMR (300 MHz, CDCl 3 ) δ 3.58 (t, 2H), 2.46-2.30 (m, 6H), 1.68-1.38 (m, 8H), 1.38-1.14 (m, 10H), 0.90 (s, 9H), 0.04 (s, 6H). CIMS m/z [M+H] + 387.0. Synthesis of 3-pentyloctyl 15-((tert-butyldimethylsilyl)oxy)-9-oxopentadecanoate (L83-6) [1127] To a solution of starting material L83-5 (600 mg, 1 eq) in DCM (18 mL) was added EDC/DMAP (1.19 g, 4 eq/ 209 mg, 1.1 eq). After stirring until the solution was clear, L1-4 (278 mg, 0.9 eq) was added in slowly. The reaction mixture was stirred at room temperature. When TLC (10% EA in Hexane, R f = 0.8) showed completion of the reaction, the solvent was reduced under vacuum to obtain crude product which was subjected to silica gel column using 0 – 10% EA in hexane as eluent to afford L83-6 as colorless oil (710 mg, 81%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.07 (t, 2H), 3.58 (t, 2H), 2.37 (t, 4H), 2.27 (t, 2H), 1.65-1.40 (m, 11H), 1.40- 1.13 (m, 29H), 0.86-0.91 (m, 15H), 0.04 (s, 6H). CIMS m/z [M+H] + 569.1. Synthesis of 3-pentyloctyl 15-hydroxy-9-oxopentadecanoate (L83-7) [1128] The starting material L83-6 (650 mg, 1 eq) was added to TBAF (1 M in THF, 10 mL). The resulting mixture was stirred at room temperature for 20 hours. When TLC (40% EA in Hexane, R f = 0.6) showed completion of the reaction, the solvent was reduced under vacuum to obtain crude product which was subjected to silica gel column using 0 – 40% EA in Hexane as eluent to afford L83-7 as colorless oil in (462 mg, 89%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.07 (t, 2H), 3.63 (t, 2H), 2.47-2.32 (m, 4H), 2.27 (t, 2H), 1.65-1.40 (m, 11H), 1.40-1.13 (m, 29H), 0.88 (t, 6H). CIMS m/z [M+H] + 455.1. Synthesis of 7,15-dioxo-15-((3-pentyloctyl)oxy)pentadecanoic acid (L83-8) [1129] The starting material L83-7 (450 mg, 1 eq) was dissolved in THF (0.5 mL) and Jones reagent was added dropwise into the reaction. The Jones reagent was dropped into the reaction mixture until the resulting dark green color did not change any more. The reaction mixture was then stirred at room temperature for 30 minutes. When TLC (EA/hexane = 1/1, R f = 0.7) showed completion of the reaction, the reaction was quenched with 2-propanol (0.5 mL), diluted with H 2 O (5 mL), and extracted by DCM (5 mL × 2). The organic fraction was reduced under vacuum to obtain crude product which was subjected to silica gel column using 0 – 50% EA in hexane as eluent to afford L83-8 as colorless oil (420 mg, 91%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.07 (t, 2H), 2.42-2.18 (m, 8H), 2.27 (t, 2H), 1.65-1.40 (m, 11H), 1.40-1.13 (m, 29H), 0.88 (t, 6H). CIMS m/z [M+H] + 469.4. Synthesis of 1-(2-(bicyclo[2.2.2]octan-1-yl)ethyl) 15-(3-pentyloctyl) 7-oxopentadecanedioate (L83-9) [1130] The starting material L83-8 (400 mg, 1 eq) and EDC/DMAP (655 mg, 4 eq/115 mg, 1.1 eq) were dissolved in DCM (15 mL). After stirring until the solution was clear, L48-1 (157 mg, 1.2 eq) was added to the above solution. The reaction mixture was monitored by TLC and stirred for 2 hours at room temperature. When TLC (EA/hexane = 1/4, R f = 0.3) showed completion of the reaction, the volatile components were reduced under vacuum to obtain crude product which was subjected to silica gel column using 0 – 20% EA in Hexane as eluent to afford L83-9 as light-yellow oil (440 mg, 86%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.16-3.98 (m, 4H), 2.48-2.33 (m, 4H), 2.31-2.21 (m, 4H), 1.69-1.47 (m, 16H), 1.47-1.06 (m, 34H), 0.88 (t, 6H). CIMS m/z [M+H] + 605.6. Synthesis of 1-(2-(bicyclo[2.2.2]octan-1-yl)ethyl) 15-(3-pentyloctyl) 7- hydroxypentadecanedioate (L83-10) [1131] A solution of starting material L83-9 (440 mg, 1 eq) in THF/MeOH (8 mL/2 mL) was cooled to 0 °C. NaBH 4 (30 mg, 1.1 eq) was then added. The resulting mixture was brought to room temperature and stirred for 3 hours. When TLC (EA/Hexane = 1/4, R f = 0.6) showed completion of the reaction, the solvent was quenched by a few drops of H 2 O, and reduced under vacuum to obtain crude product which was then subjected to silica gel column chromatography using 0 – 20% EA in Hexane as eluent to afford L83-10 as light-yellow oil (360 mg, 82%). 1 H- NMR (300 MHz, CDCl 3 ) δ 4.16-3.98 (m, 4H), 3.54 (bs, 1H), 2.31-2.21 (m, 4H), 1.69-1.47 (m, 14H), 1.47-1.06 (m, 40H), 0.88 (t, 6H). CIMS m/z [M+H] + 607.5. Synthesis of 1-(2-(bicyclo[2.2.2]octan-1-yl)ethyl) 15-(3-pentyloctyl) 7-((4- (dimethylamino)butanoyl)oxy)pentadecanedioate (Compound 72) [1132] Hydrochloric 4-(dimethylamino) butanoic acid (66 mg, 1.2 eq), DIPEA (0.1 mL) and DMAP (57 mg, 1.1 eq) were added to DCM (10 mL). The mixture was stirred until the solution was clear, then EDC (253 mg, 4 eq) was added. The reaction was stirred at room temperature for 10 minutes, and the starting material L83-10 (200 mg, 1 eq), dissolved in DCM, was added to the above solution. The reaction mixture was stirred for 5 hours at room temperature and concentrated under vacuum. The obtained crude product was then subjected to silica gel column using 0 – 10% MeOH in DCM with 1% NH 3 •H 2 O as eluent to afford Compound 72 as light-yellow oil (210 mg, 88%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.85 (quint, 1H), 4.05 (q, 4H), 2.38-2.19 (m, 12H), 1.81 (quint, 2H), 1.65-1.44 (m, 16H), 1.42-1.10 (m, 38H), 0.88 (t, 6H). CIMS m/z [M+H] + 720.6. Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 5 min, then 100% for 10 min. Flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 6.10 min, purity: >99%; UPLC column: Thermo Scientific Hypersil GOLD C18, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 40% to 100% in 5 min, then 100% for 15 min. Flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 12.67 min, purity: >99%. Synthesis of Compound 73 Synthesis of 1-((tert-butyldimethylsilyl)oxy)tetradec-13-en-5-ol (L84-2) [1133] Preparation of Grignard reagent: Magnesium turnings (1.4 g, 58.44 mmol) was put in a 250 mL round bottom flask and purged with nitrogen for 15 min. THF (3 mL), I 2 (20 mg) and 1,2-dibromoethane (100 μL) were added in sequence under nitrogen. The reaction was sealed and stirred for 3 min. L84-1 (9.16 g, 29.22 mmol) in ether solution was dropped into the reaction mixture. The mixture was stirred at room temperature for 1 h and refluxed for another hour. The dark grey solution was first cooled down to room temperature and then in ice-water bath. L83-2 (1.5 g, 9.74 mmol) in ether was added dropwise and the resulting mixture was stirred at room temperature overnight under nitrogen. Reaction mixture was cooled in ice-water bath again and quenched with sat. NH 4 Cl solution (50 mL). Reaction mixture was extracted twice with ethyl acetate (150 mL, 100 mL). Organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to obtain crude product, which was purified by flash chromatography (SiO2: 0-10% EtOAc in hexane gradient) to yield L84-2 as colorless oil (2.2 g, 66% yield). 1 H-NMR (300 MHz, CDCl 3 ) δ 5.79 (m, 1H), 4.94 (m, 2H), 3.61 (m, 3H), 2.02 (m, 4H), 1.28-2.57 (m, 20H), 0.88 (s, 9H), 0.03 (s, 6H). CIMS m/z [M+H] + 343.0, 325.1 (- H 2 O). Synthesis of 13-((tert-butyldimethylsilyl)oxy)-9-oxotridecanoic acid (L84-3) [1134] To a solution of A84-2 (2.0 g, 5.8 mmol) in a mixture of 1,2-dichloroethane (30 mL) and water (30 mL), RuCl 3 (38% in water, 163 mg, 5 mol%) and NaIO 4 (3.7 g, 17.4 mmol) were added to the reaction mixture successively and the resulting mixture was stirred at room temperature overnight. More of RuCl 3 (100 mg) NaIO 4 (2.47 g) were added and stirring continued for 24 hours. Ethyl acetate (150 mL) was added to the reaction mixture, filtered through celite and organic layer was washed with Na 2 S 2 O 3 solution (100 mL) and brine (100 mL). Organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to obtain crude product which was purified by flash chromatography (SiO 2 : 0-30% EtOAc in hexane gradient) to yield L84-3 as colorless oil (1.12 g, 54% yield). 1 H-NMR (300 MHz, CDCl3) δ 3.59 (t, J = 6.33 Hz, 2H), 2.34 (m, 6H), 1.6 (m, 8H), 1.28 (m, 6H), 0.86 (s, 9H), 0.03 (s, 6H), CIMS m/z [M+H] + 359.0, 341.0 (-H 2 O), [M-H] + 357.0, 392.9 (+2H 2 O). Synthesis of 3-pentyloctyl 13-((tert-butyldimethylsilyl)oxy)-9-oxotridecanoate (L84-4) [1135] To a solution of L84-3 (1.0 g, 2.79 mmol) in DCM (20 mL) was added DMAP (170 mg, 1.39 mmol) and EDC (1.06 g, 5.58 mmol). Reaction mixture was stirred at room temperature for 15 min. L1-4 (668 mg,l 3.34 mmol) in DCM was added and the reaction mixture was stirred at room temperature for 3h. Reaction mixture was diluted with DCM (50 mL), washed with water (25 mL) and brine (25 mL). DCM layer was dried over anhydrous Na 2 SO 4 . DCM layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain crude residue which was purified by flash chromatography (SiO 2 : 0-5% ethyl acetated in hexane gradient) to yield L84-4 as colorless oil (1.18 g, 78%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.06 (t, J = 7.14 Hz, 2H), 3.59 (t, J = 6.33 Hz, 2H), 2.38 (m, 4H), 2.27 (t, J = 7.68 Hz, 2H), 1.52-1.59 (m, 10H), 1.24-1.29 (m, 23H), 0.87 (m, 15H), 0.03 (s, 6H), CIMS m/z [M+H] + 541.1. Synthesis of 3-pentyloctyl 13-hydroxy-9-oxotridecanoate (L84-5) [1136] To a solution of L84-4 (1.18 g, 2.18 mmol) in anhydrous THF (10.0 mL) in a teflon r.b. flask was added HF.Py (5.0 mL) at 0-5°C (ice-water bath). Reaction mixture was warmed to room temperature and stirred for 1h. The reaction mixture was diluted with DCM (100 mL) and washed with sat. NaHCO 3 solution until water layer pH shows basic (> 7.0) with pH paper. Washed with Sat. brine (15 mL). Organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain crude product. Crude product was purified by flash chromatography (SiO 2 : 0-20% EtOAc in hexane gradient) to yield 800 mg (86% yield) of L84-5 as colorless oil. 1 H-NMR (300 MHz, CDCl 3 ) δ 4.06 (t, J = 7.14 Hz, 2H), 3.61-3.65 (m, 2H), 2.42 (m, 4H), 2.27 (t, J = 7.41 Hz, 2H), 1.52-1.59 (m, 11H), 1.24-1.29 (m, 23H), 0.87 (m, 6H). Synthesis of 5,13-dioxo-13-((3-pentyloctyl)oxy)tridecanoic acid (L84-6) [1137] Jones reagent (Aldrich) was added dropwise to a stirred solution of L84-5 (0.8 g,1.87 mmol) in acetone (10 mL) at ice-water bath, the addition is continued until characteristic orange color of the reagent persist for about 20 min. Reaction mixture was stirred at r.t. for 2 hr. The excess oxidant was destroyed with isopropanol (1.0 mL) and the solvents was removed under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL). Ethyl acetate was separated, and water layer was extracted with ethyl acetate (50 mL). the combined ethyl acetate layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain crude product. Crude product was combined with another 70 mg crude compound and purified by flash chromatography (SiO 2 : 0-50% EtOAc in hexane gradient) to yield 700 mg (85% yield) of L84-6 as colorless oil. 1 H-NMR (300 MHz, CDCl 3 ) δ 4.07 (t, J = 7.14 Hz, 2H), 2.49 (t, J = 7.41 Hz, 2H), 2.35-2.41 (m, 4H), 2.27 (t, J = 7.41 Hz, 2H), 1.84-1.94 (m, 2H), 1.50-1.59 (m, 6H), 1.24-1.29 (m, 24H), 0.87 (m, 6H). CIMS m/z [M+H] + 441.3.0, 323.3 (-H 2 O). Synthesis of 1-(2-(bicyclo[2.2.2]octan-1-yl)ethyl) 13-(3-pentyloctyl) 5-oxotridecanedioate (L84-7) [1138] To a solution of L84-6 (700 mg, 1.59 mmol) in DCM (20 mL) was added DMAP (193 mg, 1.59 mmol) and EDC (1.21 g, 6.36 mmol) at room temperature under nitrogen atm. Reaction mixture was stirred at room temperature for 10 min. L48-1 (292 mg, 1.9 mmol) in DCM (2.0 mL) was added and reaction mixture was stirred at room temperature for 3h. Reaction mixture was diluted with DCM (50 mL), washed with water (25 mL) and brine (25 mL). DCM layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain crude residue, which was purified by flash chromatography (SiO 2 : 0-10% ethyl acetated in hexane gradient) to yield L84-7 as colorless oil (750 mg, 82% yield). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.05 (m, 4H), 2.42 (t, J = 7.14 Hz, 2H), 2.34 (t, J = 7.71 Hz, 2H), 2.24-2.29 (m, 4H), 1.84-1.91 (m, 2H), 1.50-1.57 (m, 12H), 1.24-1.37 (m, 32H), 0.87 (m, 6H). CIMS m/z [M+H] + 577.5. Synthesis of 1-(2-(bicyclo[2.2.2]octan-1-yl)ethyl) 13-(3-pentyloctyl) 5- hydroxytridecanedioate (L84-8) [1139] To a solution of L84-7 (750 mg, 1.3 mmol) in a mixture of THF:MeOH (10 mL, 8:1) at 0°C was added NaBH 4 (98 mg, 2.6 mmol). Reaction mixture was stirred at room temperature for 2h and quenched with water (2.0 mL). Solvent was reduced under vacuum, ethyl acetate (50 mL) was added to reaction mixture and washed with water (25 mL), brine (25 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain crude product. Crude product was purified by flash chromatography (SiO 2 : 0-20% EtOAc in hexane gradient) to yield L84-8 as colorless oil (600 mg, 79% yield). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.07 (m, 4H), 3.59 (m, 1H), 2.25-2.3 (m, 4H), 1.46-1.55 (m, 18H), 2.24-2.39 (m, 52H), 0.87 (m, 6H). CIMS m/z [M+H] + 579.5. Synthesis of 1-(2-(bicyclo[2.2.2]octan-1-yl)ethyl) 13-(3-pentyloctyl) 5-((4- (dimethylamino)butanoyl) oxy)tridecanedioate (Compound 73) [1140] To a solution of N, N-dimethyl butyric acid (207 mg, 1.24 mmol) in DCM (15 mL) was added DMAP (126 mg, 1.03 mmol) and EDC (793 mg, 4.14 mmol) at room temperature under nitrogen. Reaction mixture was stirred at room temperature for 10 min. L84-8 (600 mg, 1.03 mmol) in DCM (5.0 mL) was added to the reaction mixture and the reaction mixture was stirred at room temperature for 3h. Reaction mixture was diluted with DCM (75 mL), washed with water (50 mL) and brine (50 mL). DCM layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to yield crude product. Crude product was purified by flash chromatography (SiO 2 : 0-20% EtOAc in Hexane (5% Et 3 N) gradient) to yield L84 as colorless oil (408 mg, 57%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.86 (m, 1H), 4.04 (m, 4H), 2.24- 2.29 (m, 8H), 2.2 (s, 6H), 1.75 (m, 2H), 1.5-1.59 (m, 18 H), 1.24-1.36 (m, 32H), 0.87 (m, 6H). CIMS m/z [M+H] + 692.5. Analytical HPLC column: Agela Durashell C18, 4.6×50 mm, 3 μm (Catalog No. DC930505-0), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 5 min, then 100% for 10 min. Flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 7.37 min, purity: >99.9%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No. 186005302), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 5 min, then 100% for 15 min. Flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 12.1 min, purity: >99.9%. Synthesis of Compound 74 Synthesis of bis(2-(bicyclo[2.2.2]octan-1-yl)ethyl) 9-oxoheptadecanedioate (L82-1) [1141] A mixture of compound L41-3 (0.65 g, 2.0 mmol), DMAP (253 mg, 2.0 mmol), EDC (1.58 g, 8.2 mmol) and 2-(bicyclo[2.2.2]octan-1-yl)ethan-1-ol (L48-1) (0.44 g, 3.1 mmol) in dichloromethane (20 mL) was stirred at room temperature for 48 h and then reduced under vacuum. The residue was dissolved in dichloromethane (300 mL) and washed with saturated NaHCO 3 , water and brine (80 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO 4, and the solvent was reduced under vacuum. The crude was purified by column chromatography (40 g SiO2: hexane/ ethyl acetate 0-25%) to obtain compound L82-1 (0.71 g, 58%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.06-4.01 (m, 4H), 2.36 (t, 4H), 2.24 (t, 4H), 1.65-1.52 (m, 20H), 1.43-1.18 (m, 30H); CIMS m/z [M+H] + 586.6. Synthesis of bis(2-(bicyclo[2.2.2]octan-1-yl)ethyl) 9-hydroxyheptadecanedioate (L82-2) [1142] To a solution of compound L82-1 (0.23 g, 0.4 mmol) in methanol cooled to 5 °C in an ice bath was added sodium borohydride (16 mg, 0.43 mmol). After addition, cooling bath was removed, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was adjusted with 1N aqueous HCl to pH 5 and the reaction mixture was concentrated in rotary evaporator. The residue was dissolved in DCM and washed with water. Organic layer dried over anhydrous Na 2 SO 4 , the solvent was reduced under vacuum, and the crude was purified by column chromatography (40 g SiO 2 : 0 to 10% Methanol in DCM gradient) to obtain compound L82-2 as colorless oil (0.69 g, 93%). 1 H-NMR (300 MHz, CDCl 3 ) 4.05 (t, 4H), 3.56 (s, 1H), 2.25 (t, 4H), 1.64-1.29 (m, 55H); CIMS m/z [M+H] + 588.6. Synthesis of bis(2-(bicyclo[2.2.2]octan-1-yl)ethyl) 9-((4-(dimethylamino)butanoyl)oxy) heptadecanedioate (Compound 74) [1143] To a solution of compound 4-dimethylaminobutaric acid (0.404 g, 2.4 mmol) in dichloromethane (10 mL) were added DMAP (296 mg, 2.4 mmol) and EDCI (0.92 g, 4.8 mmol), followed by compound L82-2 (0.71 g, 1.2 mmol). The reaction mixture was stirred at room temperature for 4 h and reduced under vacuum. The residue was dissolved in dichloromethane (200 mL) and washed with brine (80 mL x 3). The organic phase was dried over anhydrous Na 2 SO 4 , the solvent was reduced under vacuum, and the crude was purified by column chromatography (40 g SiO2: 5% triethylamine in hexane/ ethyl acetate 0-25%) to get final Compound 74 as colorless oil (0.65 g, 76%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.88-4.80 (m, 1H), 4.04 (t, 4H), 2.42-2.20 (m, 9H), 2.16 (s, 6H), 1.82-1.47 (m, 25H), 1.41-1.25 (m, 30H); CIMS m/z [M+H] + 702.6. Analytical HPLC column: Agela Durashell C18, 3 μm (Catalog No. DC930505-0), 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 7.38 min, purity: > 99%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No. 186005302), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 11.2 min, purity: > 94.3%.
Synthesis of Compound 75 Synthesis of 3-pentyloctyl 8-bromooctanoate (L103-2) [1144] A solution of L103-1 (3.58 g, 16.04 mmol) in DCM (50 mL) EDC (7.08 g, 37.02 mmol) and DMAP (1.52 g, 12.34 mmol) was left to stir for 20 min before 3-pentyloctan-1-ol (2.48 g, 12.34 mmol) was added in a DCM solution (10 mL). After 3 h the reaction mixture was concentrated under reduced pressure and purified using column chromatography (SiO 2 :40g, 0-2% ethyl acetate in hexane gradient) to afford L103-2 as clear colorless oil (4.01 g, 80%). 1H-NMR (300 MHz, CDCl 3 ) δ 4.08 (t, J = 7.2 Hz, 2H), 3.40 (t, J = 6.7 Hz, 2H), 2.28 (t, J = 7.4 Hz, 2H), 1.85 (t, J = 7.3 Hz, 2H), 1.64-1.53 (m, 4H), 1.45-1.21 (m, 23H), 0.88 (t, J = 6.9 Hz, 6H). Synthesis of 3-pentyloctyl 8-((4-hydroxybutyl)amino)octanoate (L103-3) [1145] To a solution of L103-2 (3.00 g, 7.39 mmol) in ethanol (30 mL), was added 4-amino- 1-butanol (6.58 g, 73.9 mmol) as a solution in ethanol (10 mL). The reaction mixture was heated to 70 °C and stirred for 20 h. The reaction mixture was concentrated under reduced pressure and the remaining residue was dissolved in DCM (100 mL). The organic layer was washed with water (50mL X 3), then brine (50mL X 3), then dried using anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified using column chromatography (SiO 2 :40g, 0-10% methanol, 0-1% NH 4 OH in dichloromethane gradient) to afford L103-3 as a clear colorless oil (1.75 g, 57%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.07 (t, J = 7.2 Hz, 2H), 3.56 (t, J = 4.8 Hz, 2H), 2.66-2.57 (m, 4H), 2.27 (t, J = 7.4 Hz, 2H), 1.68-1.46 (m, 10H), 1.27 (d, J = 16.8 Hz, 23H), 0.87 (t, J = 6.7 Hz, 6H). CIMS m/z [M+H] + 414.0. Synthesis of 8-bromooctyl 2-((3r,5r,7r)-adamantan-1-yl)acetate (L103-5) [1146] To a solution of adamantane-1-acetic acid (1.76 g, 9.08 mmol) in DCM (50 mL), was added EDC (5.20 g, 27.24 mmol) and DMAP (1.11 g, 9.08 mmol). The reaction was stirred for 20 min before L103-4 (2.47 g, 11.80 mmol) was added as a DCM solution (10 mL). After 20 h, the reaction mixture was concentrated under reduced pressure and purified using column chromatography (SiO 2 : 40 g, 0-2% ethyl acetate in hexane gradient) to afford L103-5 as a clear colorless oil (2.33 g, 65%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.04 (t, J = 6.6 Hz, 2H), 3.41 (t, J = 6.9 Hz, 2H), 2.06 (s, 2H), 1.97 (s, 3H), 1.84 (q, J = 7.2 Hz, 2H), 1.73-1.57 (m, 14H), 1.45- 1.31 (m, 8H). Synthesis of 3-pentyloctyl 8-((8-(2-((3r,5r,7r)-adamantan-1-yl)acetoxy)octyl)(4- hydroxybutyl)amino)octanoate (Compound 75) [1147] To a solution of L103-3 (1.75 g, 4.24 mmol) and L103-5 (2.29 g, 5.94 mmol) in CPME and ACN (1:1, 30 mL) was added KI (0.70 g, 4.24 mmol) and K 2 CO 3 (1.76 g, 12.72 mmol). The reaction mixture was heated to 90 °C and stirred for 90 h. The reaction mixture was concentrated under reduced pressure and the product was purified using column chromatography (SiO 2 : 80 g, 0-10 % methanol, 1% NH 4 OH in dichloromethane gradient) to afford Compound 75 as colorless oil (1.95 g, 64%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.07-4.01 (m, 4H), 3.48-3.58 (2H), 2.41 (t, J = 7.8 Hz, 6H), 2.27 (s, 2H), 2.06 (s, 2H), 1.96 (s, 3H), 1.68- 1.55 (m, 28H), 1.31-1.25 (m, 29H), 0.88 (t, J = 6.9 Hz, 6H). CIMS m/z [M+H] + 719.0. Analytical HPLC column: Agela Durashell C18, 4.6×50 mm, 3 μm (Catalog No. DC930505- 0), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 5 min, then 100% for 10 min. Flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 6.78 min, purity: > 99%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No. 186005302), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 5 min, then 100% for 15 min. Flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 11.22 min, purity: > 99%.
Synthesis of Compound 79 Synthesis of dec-9-enal (L113-2) [1148] To a stirring solution of L113-1 in DCM (200 mL) under nitrogen, was added Dess- Martin periodinane (39.08 g, 92.15 mmol), and the reaction mixture was stirred at 0°C for 1 h and at RT for another 2 h. The reaction was quenched with a sat. aq. solution of sodium thiosulfate (100 mL) and sat. aq. solution of NaHCO 3 until the pH was neutral (250 mL). The organic layer was separated, and the aqueous layer was further extracted with DCM (2 X 150 mL). The organic layers were combined and washed with water (150 mL X 3) and brine (150 mL X 3), then it was dried over anhydrous sodium sulfate. The organic layer was then concentrated under reduced pressure, and the residue was purified using column chromatography (SiO 2 : 320g using a gradient of 0-10% EtOAC in hexanes). The fractions containing the product were combined and concentrated to afford L113-2 as colorless oil (9.02 g, 76%). 1 H-NMR (300 MHz, CDCl 3 ) δ 9.76 (t, J = 1.8 Hz, 1H), 5.84-5.73 (m, 1H), 5.02-4.90 (m, 2H), 2.42 (td, J = 7.3, 1.8 Hz, 2H), 2.03 (q, J = 7.0 Hz, 2H), 1.61 (q, J = 7.2 Hz, 2H), 1.37- 1.31 (m, 8H). Synthesis of 1-((tert-butyldimethylsilyl)oxy)tetradec-13-en-5-ol (L113-3) [1149] Magnesium turnings (4.07 g, 167.65 mmol) was put in a 250 mL round bottom flask and purged with nitrogen for 15 min. Diethyl ether (40 mL), iodine (20 mg) and 1,2- dibromoethane (100 μL) were added in sequence under nitrogen. The reaction was sealed and stirred for 15 min. Tert-butyl(4-iodobutoxy)dimethylsilane (26.34 g, 83.82 mmol) in ether solution (20 mL) was dropped into the reaction mixture. The mixture was stirred at room temperature for 1 h and refluxed for another hour. The dark grey solution was first cooled down to room temperature and then in an ice-water bath. L113-2 (4.31 g, 27.94 mmol) in ether was added dropwise and the resulting mixture was stirred at room temperature overnight under nitrogen. Reaction mixture was cooled in ice-water bath again and quenched with sat. aq. NH 4 Cl solution (200 mL). Reaction mixture was extracted with ethyl acetate (200 mL X 3). The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain crude product, which was purified by flash chromatography (SiO2: 220 g, 0-10% EtOAc in hexane gradient) to yield L113-3 as colorless oil (5.5 g, 57%). 1 H-NMR (300 MHz, CDCl 3 ) δ 5.58-5.93 (1H), 4.76-5.10 (2H), 3.39-3.81 (3H), 1.90-2.14 (2H), 1.36 (dd, J = 23.0, 18.3 Hz, 18H), 0.89 (t, J = 2.8 Hz, 9H), 0.04 (s, 6H). CIMS m/z [M+H] + 343, 325 (-H 2 O). Synthesis of 1-((tert-butyldimethylsilyl)oxy)tetradec-13-en-5-one (L113-4) [1150] To a solution of L113-3 (2.50 g, 7.30 mmol) in DCM (20 mL) in an ice bath, was added Dess-Martin reagent (1.20 g, 8.76 mmol). The reaction mixture was taken out of the ice bath and left to stir at room temperature for 4 h. The reaction mixture was quenched with a sat. aq. solution of sodium thiosulfate (30 mL) and sat. aq. solution of sodium bicarbonate (30 mL). The reaction mixture was then extracted with ethyl acetate (50 mL X 3) and the organic layer was washed with water (50 mL X 3), then brine (50 mL X 3) then it was dried with anhydrous sodium sulfate and concentrated under reduced pressure leaving behind 4.01 g of L113-4 as a crude material which was used in the next step without any further purification. CIMS m/z [M+H] + 341.3. Synthesis of 13-((tert-butyldimethylsilyl)oxy)-9-oxotridecanoic acid (L113-5) [1151] In a 50 mL RBF, sodium periodate (6.23 g, 19.12 mmol) was added followed by phosphate buffer (pH 7.2, 30 mL) and the mixture was left to stir until a clear solution was observed. After that, KMnO 4 (1.15 g, 7.28 mmol) was added, and the mixture was left to stir for 15 min. In another 50 mL RBF containing the crude of L113-4 (4.01 g), tert-butanol (30 mL) was added followed by the permanganate solution and the reaction mixture was left to stir for 3 h. The reaction was quenched with saturated aqueous solution of sodium thiosulfate (100 mL) and the product was extracted using ethyl acetate (200 mL X 3). The organic layer was washed with saturated aqueous solution of sodium sulfate (100 mL X 1), saturated aqueous solution of ammonium chloride (100 mL X 3), and brine (100mL X 3). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure then purified with flash chromatography (SiO2: 40 g, 0-10% methanol in dichloromethane gradient) to afford L113-5 as a colorless oil (2.44 g, 93%). 1 H-NMR (300 MHz, CDCl 3 ) δ 3.60 (s, 2H), 2.41-2.33 (m, 6H), 1.61-1.51 (m, 8H), 1.27 (d, J = 16.0 Hz, 6H), 0.87 (s, 9H), 0.03 (s, 6H). CIMS m/z [M+H] + 359.3. Synthesis of 3-pentyloctyl 13-((tert-butyldimethylsilyl)oxy)-9-oxotridecanoate (L113-6) [1152] To a solution of L113-5 (2.44 g, 6.80 mmol) in DCM (20 mL), was added DMAP (831 mg, 6.80 mmol) and EDC (3.26 g, 17.01 mmol). The reaction mixture was stirred at room temperature for 15 min.3-Pentyloctan-1-ol (1.36 g, 6.80 mmol) in DCM (5 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain crude residue which was purified by flash chromatography (SiO 2 : 40 g, 0-5% ethyl acetated in hexane gradient) to yield L113-6 as colorless oil (1.65 g, 45%). 1 H-NMR (300 MHz, CDCl 3 ) 4.07 (s, 2H), 3.60 (s, 2H), 2.39 (d, J = 10.2 Hz, 4H), 2.27 (s, 2H), 1.57-1.55 (m, 10H), 1.27 (d, J = 13.5 Hz, 23H), 0.90-0.85 (m, 15H), 0.04 (s, 6H). CIMS m/z [M+H] + 541.5. Synthesis of 3-pentyloctyl 13-hydroxy-9-oxotridecanoate (L113-7) [1153] To a 250 mL RBF containing a solution of L113-6 (1.65 g, 3.05 mmol) in THF (10 mL), was added a solution of TBAF in THF (1M, 10 mL). The reaction was left to stir at RT for 1 h. The reaction mixture was concentrated under reduced pressure and purified using column chromatography (SiO 2: 40 g, 0-50% ethyl acetate in hexane gradient) to yield L113-7 as a colorless oil (1.28 g, 98%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.07 (t, J = 7.0 Hz, 2H), 3.63 (t, J = 5.9 Hz, 2H), 2.42 (dt, J = 16.4, 7.2 Hz, 4H), 2.27 (t, J = 7.4 Hz, 2H), 1.69-1.53 (m, 10H), 1.27 (d, J = 14.9 Hz, 23H), 0.91-0.85 (m, 6H); CIMS m/z [M+H] + 409.4 (-H 2 O). Synthesis of 5,13-dioxo-13-((3-pentyloctyl)oxy)tridecanoic acid (L113-8) [1154] Jones reagent (chromium trioxide in diluted sulfuric acid) was added dropwise to a stirred solution of L113-7 (1.28 g, 3.00 mmol) in acetone (20 mL) at ice-water bath. The addition was continued until the characteristic orange color of the reagent persisted for about 20 min. Reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with isopropanol (20 mL) and water (50 mL). The reaction mixture was concentrated under reduced pressure. The concentrated solution was further diluted with water (50 mL), then the product was extracted with dichloromethane (100 mL X 4). The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain L113-8 as colorless oil (1.26 g, 95%). 1 H-NMR (300 MHz, CDCl3) δ 7.26 (s, 2H), 4.07 (t, J = 7.0 Hz, 2H), 2.49 (t, J = 7.0 Hz, 2H), 2.38 (td, J = 7.2, 2.1 Hz, 4H), 2.27 (t, J = 7.4 Hz, 2H), 1.89 (t, J = 7.2 Hz, 2H), 1.56 (q, J = 6.8 Hz, 6H), 1.27 (d, J = 14.3 Hz, 23H), 0.87 (t, J = 6.9 Hz, 6H). CIMS m/z [M+H] + 441.4. Synthesis of 1-(bicyclo[2.2.2]octan-1-ylmethyl) 13-(3-pentyloctyl) 5-oxotridecanedioate (L113-9) [1155] To a solution of L113-8 (1.22 g, 2.77 mmol) in DCM (25 mL) was added DMAP (307 mg, 2.52 mmol) and EDC (1.93 g, 10.07 mmol) at room temperature under nitrogen atm. The reaction mixture was stirred at room temperature for 20 min. Bicyclo[2.2.2]octan-1- ylmethanol (353 mg, 2.52 mmol) in DCM (5.0 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain crude residue, which was purified by flash chromatography (SiO 2 : 40 g, 0- 5% ethyl acetated in hexane gradient) to yield L113-9 as colorless oil (1.12, 79% yield). 1 H- NMR (300 MHz, CDCl 3 ) δ 4.07 (t, J = 7.2 Hz, 2H), 3.67 (s, 2H), 2.48-2.24 (m, 8H), 1.88 (t, J = 7.2 Hz, 2H), 1.59-1.53 (m, 14H), 1.42-1.24 (m, 28H), 0.87 (t, J = 6.7 Hz, 6H). Synthesis of 1-(bicyclo[2.2.2]octan-1-ylmethyl) 13-(3-pentyloctyl) 5-hydroxytridecanedioate (L113-10) [1156] To a solution of L113-9 (1.12 g, 1.99 mmol) in a mixture of THF and MeOH (50 mL, 4:1) at 0°C was added NaBH 4 (151 mg, 3.98 mmol). The reaction mixture was stirred at room temperature for 1h and quenched with ice cold HCl (1N) until the solution reached pH 6. The THF was evaporated, and the product was extracted with dichloromethane (30 mL X 3). The organic layer was then washed with water (30 mL X 3), brine (30 mL X 3), then dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain crude product. Crude product was purified by flash chromatography (SiO 2 : 0-20% EtOAc in hexane gradient) to yield L113-10 as colorless oil (850 mg, 76% yield). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.07 (s, 2H), 3.68 (s, 2H), 3.51-3.65 (1H), 2.34-2.28 (m, 4H), 1.57-1.53 (m, 14H), 1.46-1.25 (m, 34H), 0.88 (t, J = 6.9 Hz, 6H). CIMS m/z [M+H] + 565.5. Synthesis of 1-(bicyclo[2.2.2]octan-1-ylmethyl) 13-(3-pentyloctyl) 5-((4-(dimethylamino) butanoyl)oxy)tridecanedioate (Compound 79) [1157] To a solution of 4-(dimethylamino)butanoic acid hydrochloride (207 mg, 1.24 mmol) in DCM (22 mL), was added DIPEA (1.0 mL, 5.74 mmol) DMAP (184 mg, 2.11 mmol), and EDC (1.15, 6.02 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 20 min. L113-10 (850 mg, 1.50 mmol) in DCM (8.0 mL) was added to the reaction mixture and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to yield crude product which was purified by flash chromatography (SiO 2 : 0-20% EtOAc in Hexane (1% Et 3 N) gradient) to yield Compound 79 as colorless oil (906 mg, 89%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.81-4.92 (1H), 4.07 (s, 2H), 3.67 (s, 2H), 2.28 (q, J = 7.8 Hz, 8H), 2.21 (s, 6H), 1.78 (s, 2H), 1.59-1.53 (m, 19H), 1.39-1.25 (m, 29H), 0.88 (t, J = 6.9 Hz, 6H). CIMS m/z [M+H] + 678.6. Analytical HPLC column: Agela Durashell C18, 4.6×50 mm, 3 μm (Catalog No. DC930505-0), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 5 min, then 100% for 10 min. Flow rate: 1mL/min, column temperature: 20±2 °C, detector: ELSD, t R = 7.33 min, purity: 99.5%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No.186005302), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 5 min, then 100% for 15 min. Flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 10.85 min, purity: 95.8%.
Synthesis of Compound 80 Synthesis of 7-((tert-butyldiphenylsilyl)oxy)heptanal (L114-2) [1158] Heptane-1,7-diol L114-1 (9.3 g, 70 mmol) was dissolved in ACN/hexane (60/180 mL), followed by addition of triethylamine (12 mL, 84 mmol) and TBDPSCl (18.3 mL, 70 mmol). The reaction mixture was then stirred at room temperature for 20 hours. The reaction mixture was then diluted by ethyl acetate (200 mL) and extracted by water (200 mL × 2). The organic fraction was evaporated to obtain crude product which was then subjected to silica gel column using 0 – 20% EA in hexane as eluent to afford L114-2 as colorless liquid (16.3 g, 63%). 1 H- NMR (300 MHz, CDCl 3 ) δ 7.72-7.58 (m, 4H), 7.49-7.30 (m, 6H), 3.72-3.50 (m, 4H), 1.65- 1.45 (m, 6H), 1.38-1.12 (m, 4H), 1.04 (s, 9H). Synthesis of 7-((tert-butyldiphenylsilyl)oxy)heptanal (L114-3) [1159] 7-((tert-butyldiphenylsilyl)oxy)heptan-1-ol L114-2 (16.3 g, 44 mmol) was dissolved in DCM (210 mL) and cooled to 0 °C, followed by addition of Dess-Martin periodinane (20.5 g, 48 mmol). The reaction mixture was then stirred at room temperature for 2 h. When TLC showed completion of the reaction, Aq. NaOH (100 mL) was added to quench the reaction. The quenched reaction mixture was then diluted with DCM and washed with water twice. The organic fraction was evaporated to obtain crude product which was then subjected to silica gel column using 0 – 10% EA in hexane as eluent to afford L114-3 as colorless liquid (11.5 g, 71%). 1 H-NMR (300 MHz, CDCl 3 ) δ 9.75 (s, 1H), 7.72-7.58 (m, 4H), 7.49-7.30 (m, 6H), 3.64 (t, 2H), 2.47-2.30 (m, 2H), 1.65-1.45 (m, 6H), 1.38-1.12 (m, 4H), 1.04 (s, 9H). Synthesis of 12-((tert-butyldiphenylsilyl)oxy)dodec-1-en-6-ol (L114-4) [1160] 7-((tert-butyldiphenylsilyl)oxy)heptanal L114-3 (11.5 g, 31 mmol) was dissolved in THF (200 mL) and purged with N 2 for 15 min. Pent-4-en-1-ylmagnesium bromide (75 mL, 3.7 mmol, 0.5 M in THF) was then added dropwise to the aldehyde solution at room temperature. The resulting reaction mixture was stirred at room temperature for another hour. When TLC showed completion of the reaction, water (10 mL) was added. The solvent was evaporated, the mixture was dissolved in EA and extracted with sat. NH 4 Cl. The organic fraction was evaporated to obtain crude product which was then subjected to silica gel column using 0 – 20% EA in hexane as eluent to afford L114-4 as colorless oil (13.5 g, 61%). 1 H-NMR (300 MHz, CDCl 3 ) δ 7.72-7.58 (m, 4H), 7.49-7.30 (m, 6H), 5.89-5.71 (m, 1H), 5.10-4.88 (m, 2H), 3.64 (t, 2H), 1.63-1.13 (m, 16H), 1.04 (s, 9H). Synthesis of 11-((tert-butyldiphenylsilyl)oxy)-5-oxoundecanoic acid (L114-5) [1161] NaIO 4 (11.4 g, 8 eq) was dissolved in water (72 mL), followed by adding ACN (48 mL) and CCl 4 (48 mL). L114-4 (3 g, 6.8 mmol) was added to the above suspension and stirred for 5 min. RuCl 3 (138 mg, 0.68 mmol) was added in one portion. The resulting reaction mixture was stirred at room temperature for 20 h. The mixture was then diluted with water (100 mL) and extracted with DCM (100 mL × 2). The organic fraction was collected and concentrated to dryness. The crude mixture was dissolved in acetone (20 mL). Jones reagent was then added slowly to the mixture until no color change can be observed. The reaction was then quenched with isopropanol (20 mL). The solvent was evaporated, and then the crude product was dissolved in DCM (50 mL) and extracted with water (50 mL × 2). The organic fraction was evaporated to obtain crude product which was then subjected to silica gel column using 0 – 10% MeOH in DCM as eluent to afford L114-5 as colorless oil (1.7 g, 55%). %). 1 H-NMR (300 MHz, CDCl 3 ) δ 7.72-7.58 (m, 4H), 7.49-7.30 (m, 6H), 3.64 (t, 2H), 2.49 (t, 2H), 2.43- 2.30 (m, 4H), 1.89 (p, 2H), 1.63-1.49 (m, 4H), 1.32-1.19 (m, 4H), 1.04 (s, 9H). CIMS m/z [M- H] + 453.2. Synthesis of (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 11-((tert-butyldiphenylsilyl) oxy)-5-oxoundecanoate (L114-6) [1162] L114-5 (1.7 g, 3.7 mmol) was dissolved in DCM (60 mL), followed by addition of EDC/DMAP (2.87 g, 15 mmol / 500 mg, 4.0 mmol). After stirring for 5 minutes, (S)-borneol (870 mg, 5.6 mmol) was added slowly to the above solution, and then the reaction mixture was stirred for 3 h at room temperature. When TLC showed completion of the reaction, the organic fraction was evaporated to obtain crude product which was subjected to silica gel column using 0 – 20% EA in hexane as eluent to afford L114-6 as colorless oil (1.6 g, 73%). 1 H-NMR (300 MHz, CDCl 3 ) δ 7.72-7.58 (m, 4H), 7.49-7.30 (m, 6H), 4.91-4.83 (m, 1H), 3.64 (t, 2H), 2.49 (t, 2H), 2.40-2.24 (m, 5H), 1.93-1.80 (m, 3H), 1.79-1.49 (m, 9H), 1.40-1.15 (m, 6H), 1.04 (s, 9H), 1.00-0.70 (m, 12H). CIMS m/z [M+H] + 591.3. Synthesis (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 11-hydroxy-5-oxoundecanoate (L114-7) [1163] The starting material L114-6 (1.6 g, 2.7 mmol) was added to TBAF (1 M in THF, 5 mL). The resulting mixture was then stirred at room temperature for 2 h. When TLC showed the completion of reaction, the solvent was evaporated to obtain crude product which was subjected to silica gel column using 0 – 60% EA in hexane as eluent to afford L114-7 as light- yellow oil (830 mg, 87%). 1 H-NMR (300 MHz, CDCl 3 ) δ 4.91-4.83 (m, 1H), 3.64 (t, 2H), 2.49 (t, 2H), 2.40-2.24 (m, 5H), 1.93-1.80 (m, 3H), 1.79-1.49 (m, 8H), 1.40-1.15 (m, 8H), 1.00-0.70 (m, 10H). Intermediate Step 1: Synthesis of 4,4-bis((3,7-dimethyloct-6-en-1-yl)oxy)butanenitrile (L4m- 2) [1164] To a 100 mL round bottom flask, 4,4-dimethoxybutanenitrile L4-1 (1 equiv), alcohol L4m-1 (~2.5 equiv) and pyridinium p-toluenesulfonate (0.05 equiv) were added. The resulting mixture was stirred at 120 °C for 4h and cooled to room temperature. EtOAc (50 mL) and H 2 O (20 mL) were added in, and the resulting phases were separated. The aqueous phase was extracted with EtOAc (50 mL). Combined organic extracts were washed with H 2 O (20 mL) and dried over anhydrous MgSO 4 . Filtration and concentration provided crude material which was purified by flash column chromatography (SiO 2 : 0 to 10% ethyl acetate in hexanes gradient) to yield L4m-2 as colorless oil (6.2 g, 73%). 1 H-NMR (300 MHz, CDCl 3 ) δ 5.08 (t, J = 7.2 Hz, 2H), 4.54 (t, J = 5.3 Hz, 1H), 3.72-3.36 (m, 4H), 2.41 (t, J = 7.3 Hz, 2H), 2.10-1.84 (m, 6H), 1.80-1.05 (m, 22H), 0.89 (d, J = 6.6 Hz, 6H). Intermediate Step 2: Synthesis of 4,4-bis((3,7-dimethyloct-6-en-1-yl)oxy)butanoic acid (L4m- 3) [1165] To a 100 mL round bottom flask containing a solution of L4m-2 (1 equiv) in ethanol (50 mL) was added a solution of KOH in water (50 mL, 3 equiv KOH). The mixture was stirred at 120 °C for 20h. The volatiles were removed, and the reaction pH was adjusted to 5. EtOAc (150 mL) and H 2 O (60 mL) were added, and the resulting phases were separated. The aqueous phase was extracted with EtOAc (50 mL). Combined organic extracts were washed with H 2 O (60 mL x 2) and dried over anhydrous MgSO 4 . Filtration and concentration provided L4m-3 as colorless oil (6.2 g, 73%). 1 H-NMR (300 MHz, CDCl 3 ) δ : 5.08 (t, J = 6.84 Hz, 2H), 4.5 (t, J = 5.22 Hz, 1H), 3.59 (m, 2H), 3.44 (m, 2H), 2.44 (t, J = 7.44 Hz, 2H), 1.94 (m, 6H), 1.54-1.67 (m, 16H), 1.35 (m, 4H), 1.13 (m, 2H), 0.87 (d, J = 6.33 Hz, 6H); CIMS m/z [M+H] + 396.2. Synthesis of (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 11-((4,4-bis((3,7- dimethyloct-6-en-1-yl)oxy)butanoyl)oxy)-5-oxoundecanoate (L114-8) [1166] The starting acetal acid (1.11 g, 2.8 mmol) was dissolved in DCM (40 mL), followed by addition of EDC/DMAP (1.8 g, 9.2 mmol /313 mg, 2.5 mmol). After stirring 5 minutes, L114-7 (820 mg, 2.3 mmol) was added slowly to the above solution and the reaction mixture was stirred for 3 h at room temperature. When TLC showed completion of the reaction, the organic fraction was evaporated to obtain crude product which was subjected to silica gel column using 0 – 20% EA in hexane as eluent to afford L114-8 as colorless oil (1.6 g, 94%). 1 H-NMR (300 MHz, CDCl 3 ) δ 5.08 (t, 2H), 4.91-4.83 (m, 1H), 4.48 (t, 1H), 4.04 (t, 2H), 3.65- 3.52 (m, 2H), 3.49-3.35 (m, 2H), 2.49 (t, 2H), 2.40-2.24 (m, 7H), 1.02-1.80 (m, 9H), 1.79-1.43 (m, 26H), 1.41-1.21 (m, 10H), 1.20-1.02 (m, 4H), 1.00-0.70 (m, 16H). Synthesis of (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 11-((4,4-bis((3,7- dimethyloct-6-en-1-yl)oxy)butanoyl)oxy)-5-hydroxyundecanoate (L114-9) [1167] L114-8 (1.6 g, 2.2 mmol) was added to THF/MeOH (24 mL/6 mL) and cooled to 0°C. NaBH 4 (95 mg, 2.4 mmol) was then added to the reaction. The resulting mixture was brought to room temperature and stirred for 3 h. When TLC showed completion of the reaction, the solvent was quenched by a few drops of H 2 O, and evaporated to obtain crude product which was then subjected to silica gel column using 0 – 20% EA in hexane as eluent to afford L114- 9 as light-yellow oil (1.45 g, 91%). 1 H-NMR (300 MHz, CDCl 3 ) δ 5.08 (t, 2H), 4.91-4.83 (m, 1H), 4.48 (t, 1H), 4.04 (t, 2H), 3.65-3.52 (m, 3H), 3.49-3.35 (m, 2H), 2.49 (t, 2H), 2.40-2.24 (m, 5H), 1.02-1.80 (m, 8H), 1.83-1.07 (m, 48H), 1.00-0.70 (m, 18H). Synthesis of (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 11-((4,4-bis((3,7- dimethyloct-6-en-1-yl)oxy)butanoyl)oxy)-5-hydroxyundecanoate (Compound 80) [1168] To a 250 mL round bottom flask was added 4-(dimethylamino) butanoic acid hydrochloride (429 mg, 2.56 mmol), EDC (1.27 g, 6.63 mmol) and DMAP (116 mg, 0.95 mmol) in anhydrous dichloromethane (20 mL) and the reaction was stirred for 10 min. To this was added N, N-diisopropylethylamine (1.23 g, 1.65 mL, 9.48 mmol) along with L114-9 (695 mg, 0.95 mmol) in anhydrous dichloromethane (10 mL) and the reaction mixture was stirred under nitrogen at room temperature for 48 h. After completion of the reaction, about 20 g of flash silica (pre-neutralized with triethylamine) was added and the contents were stirred well to yield a uniform mixture. Solvent was removed from this mixture under vacuum. The residue was loaded on to an empty flash cartridge, which was then attached to a flash purification system loaded with 40 g flash silica column (equilibrated with 1 % triethylamine in hexane) and was purified by flash chromatography (SiO 2 : ethyl acetate/hexane (with 1 % triethylamine) 0-20 %) to get Compound 80 as a clear oil (634 mg, 79 %). 1 H-NMR (300 MHz, CDCl 3 ) δ: 5.10 (t, J = 7.0 Hz, 2H), 4.94-4.86 (m, 2H), 4.55 (t, J = 7.0 Hz, 1H), 4.04 (t, J = 7.0 Hz, 2H), 3.65-3.46 (m, 4H), 2.41-3.28 (m, 8H), 2.20 (s, 6H), 2.05-1.71 (m, 10H), 1.68-1.47 (m, 27H), 1.35-1.08 (m, 14H), 0.96-0.81 (m, 15H); CIMS m/z [M+H] + 846.6. Analytical HPLC column: Agela Durashell C18, 4.6×50 mm, 3 μm (Catalog No. DC930505-0), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 70% to 100% in 5 min, then 100% for 10 min. Flow rate: 1mL/min, column temperature: 20±2 °C, ELSD, t R = 8.4 min, purity: > 99%; UPLC column: Waters Aquity UPLC® CSHTM, C18, 1.7 μm, 3.0×150 mm, (Part No.186005302), mobile phase A: acetonitrile with 0.1% trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroacetic acid, use gradient: A in B 5% to 95% in 15 min, flow rate: 1mL/min, column temperature: 20±2 °C, detector: CAD, t R = 12.13 min, purity: 94.13 %. Example 2. Methods of Making the Delivery Vehicles [1169] The delivery vehicles such as LNPs of the present disclosure may be prepared using any convenient methodology. In one non-limiting example, the LNPs are formed by mixing equal volumes of lipids dissolved in alcohol with oligonucleotide payloads dissolved in a citrate buffer by an impinging jet process. [1170] The lipid solution contains a cationic lipid compound of the present disclosure, a helper lipid, a neutral lipid and a PEGylated lipid. The payload to total lipid ratio is approximately 1:20 (wt/wt). The LNPs are formed by mixing equal volumes of lipid solution in ethanol with oligonucleotide payloads dissolved in a citrate buffer by an impinging jet process through a mixing device. The mixed LNP solution is held at room temperature for 0-24 hrs prior to a dilution step. [1171] The solution is then concentrated and diafiltered with suitable buffer by ultrafiltration or dialysis process using membranes. The final product is sterile filtered and stored at 4° C. Example 3. Evaluation of Candidate LNP Targeting Systems [1172] A library of candidate targeting systems is prepared where the candidate targeting systems comprise at least one identifier sequence or moiety in the formulation and at least one identifier sequence and/or payload in the nucleic acid construct. Example 4. LNP Formulations A [1173] Ionizable lipids, DSPC, cholesterol, and PEG2K-DMG were dissolved in pure ethanol at a 48.5:10:39:2.5 mol% ratio with a total lipid concentration of 10.8 mM. A 0.10 mg/mL mRNA solution was prepared using acidic buffer (pH 4.0-5.0) containing mRNA encoding human erythropoietin (hEPO) and firefly luciferase (fLuc) (1:2 ratio). The nucleotide and lipid solutions were mixed at a 3:1 volume ratio using the NanoAssemblr microfluidic system at a 12 mL/min total flow rate resulting in rapid mixing and self-assembly of LNPs. Formulations were further dialyzed against PBS (pH 7.4) overnight at 4 °C, concentrated using centrifugal filtration and filtered (0.2 μm pore size). The particle size and polydispersity index (PDI) of formulations was measured by dynamic light scattering (DLS) using a Zetasizer Ultra (Malvern Panalytical). RNA encapsulation efficiency (EE%) was determined by Ribogreen assay. Table 47: LNP Formulations
Buffer A: 25 mM Sodium Acetate, pH 5.0; Buffer B: 50 mM Citrate, pH 4.0 Example 5. LNP Formulations B [1174] Ionizable lipids, DSPC, cholesterol, and PEG2K-DSPE were dissolved in pure ethanol at a 48.5:10:40:1.5 mol% ratio with a total lipid concentration of 10.8 mM. A 0.10 mg/mL mRNA solution was prepared using acidic buffer (pH 4.0-5.0) containing mRNAs encoding firefly luciferase (fLuc). The nucleotide and lipid solutions were mixed at a 3:1 volume ratio using the NanoAssemblr microfluidic system at a 12 mL/min total flow rate resulting in rapid mixing and self-assembly of LNPs. Formulations were further dialyzed against PBS (pH 7.4) overnight at 4 °C, concentrated using centrifugal filtration and filtered (0.2 μm pore size). The particle size and polydispersity index (PDI) of formulations was measured by dynamic light scattering (DLS) using a Zetasizer Ultra (Malvern Panalytical). RNA encapsulation efficiency (EE%) was determined by Ribogreen assay. Table 48: LNP Formulations F-17 Cmpd 71 C 139.3 0.134 72.1 F-18 Cmpd 72 B 144.4 0.047 88.9 F-19 Cmpd 73 B 174.4 0.009 77.2 F -20 Cmpd 74 B 181.7 0.015 84.7 F -21 Cmpd 78 A 108.4 0.067 80.9 Buffer A: 25 mM Sodium Acetate, pH 5.0; Buffer B: 50 mM Citrate, pH 4.0; Buffer C: 100 mM Citrate, pH 4.0 Example 6. hEPO and fLUC in vivo reporter assays [1175] Balb/cAnNCrl (female, 6-8 weeks) were administrated with LNPs (formulated for a 0.3 mg/kg hEPO/fLuc mRNA dose, see Example 5-A) by intravenous injection. Plasma samples were harvested at 5, 23 and 48 hours post dose for hEPO analysis. Bioluminescence imaging (BLI) of the mice was taken at 6, 24 and 48 hours post-dosing using an IVIS Lumina III LT system (PerkinElmer) after injection of D-luciferin solution (150 mg/kg, intraperitoneal injection (IP)). hEPO concentrations were measured using an ELISA kit (DEP00, R&D Systems). The maximal concentration or BLI signal (Cmax) and area under concentration vs time curve (AUC) of the individual mouse plasma hEPO or whole body BLI data was calculated using a non-compartment analysis (NCA) program (WinNonlin ® , Version 8.3.4 [Pharsight Corp (Mountain View, CA, USA)]). [1176] Table 49 reports the hEPO concentration at 5 hours and the AUC over the 48 hour period after dosing, both overall and as normalized to an internal standard across experiments, for each formulation tested. Table 49 also reports the luciferase bioluminescence imaging measured at 6 hours and the AUC over the 48 hour period after dosing, for each formulation tested. Data keys: Luciferase BLI C6hr (photons/sec): # = <100 million p/s; 100 million p/s ≤ ## < 1 billion p/s; 1 billion p/s ≤ ### < 10 billion p/s; 10 billion p/s ≤ #### < 100 billion p/s; 100 billion p/s ≤ ##### < 1 trillion p/s Luciferase BLI AUC48hr (hr*photons/sec): $ < 10 billion hr*p/s; 10 billion hr*p/s ≤ $$ < 100 billion hr*p/s; 100 billion hr*p/s ≤ $$$ < 1 trillion hr*p/s; 1 trillion hr*p/s ≤ $$$$ < 10 trillion hr*p/s Table 49: In Vivo Assay Data Example 7. In Vivo Organ Tropism assays [1177] Balb/cAnNCrl (female, 6-8 weeks) were dosed with LNP formulations (formulated for a 0.2 mg/kg fLuc mRNA dose, see Example 5B) by IV injection. At 6 hour post LNP dose, the mice were injected with D-luciferin solution (150 mg/kg, intraperitoneal (IP)).10 minutes post D-luciferin dosing, mice were sacrificed and organs (liver, spleen, lung, kidney, and heart or brain) were harvested. Bioluminescence imaging of the organs from each dosing groups were taken simultaneously using an IVIS Lumina III LT system (PerkinElmer). [1178] The sum of the bioluminescence of all organs from each individual mouse were summed as the total flux (photons/second). The percentage of bioluminescence of each individual organ was calculated to determine the organ tropism of the LNP formulations. [1179] Luciferase BLI C6hr (photons/sec): # = <100 million p/s; 100 million p/s ≤ ## < 1 billion p/s XII. EQUIVALENTS AND SCOPE [1180] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments in accordance with the disclosure described herein. The scope of the present disclosure is not intended to be limited to the above Description, but rather is as set forth in the appended claims. [1181] In the claims, articles such as "a," "an," and "the" may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or the entire group members are present in, employed in, or otherwise relevant to a given product or process. [1182] It is also noted that the term "comprising" is intended to be open and permits but does not require the inclusion of additional elements or steps. When the term "comprising" is used herein, the term "consisting of" is thus also encompassed and disclosed. [1183] The term "about" as used herein, means within ±10% of a given value or range. Thus, "about 10" means 9 to 11. [1184] Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. [1185] In addition, it is to be understood that any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the compositions of the disclosure (e.g., any antibiotic, therapeutic or active ingredient; any method of production; any method of use; etc.) can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art. [1186] It is to be understood that the words which have been used are words of description rather than limitation, and that changes may be made within the purview of the appended claims without departing from the true scope and spirit of the disclosure in its broader aspects. [1187] While the present disclosure has been described at some length and with some particularity with respect to the several described embodiments, it is not intended that it should be limited to any such particulars or embodiments or any particular embodiment, but it is to be construed with references to the appended claims so as to provide the broadest possible interpretation of such claims in view of the prior art and, therefore, to effectively encompass the intended scope of the disclosure.
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