Lipid nanoparticles comprising coding RNA molecules for use in gene editing and as vaccines and therapeutic agents

Abstract

The present disclosure describes improved LNP-based RNA vaccines, nucleobase editing systems, and therapeutics for use in treating and / or immunization against disease. In particular, the disclosure describes improved LNPs, including novel and improved ionizable lipids for making LNPs, that enhance the targeted delivery of LNP-based RNA vaccines and therapeutics based on linear and / or circular mRNAs. The improved LNPs protect linear and / or circular mRNA payloads from degradation and clearance while achieving targeted systemic or local delivery for use as enhanced vaccines and / or therapeutic agents.

Description

This disclosure describes improved LNP-based RNA vaccines, nucleobase editing systems, and therapeutic agents for the treatment and / or immune diseases. Specifically, this disclosure describes improved LNPs, including novel and improved ionizable lipids for manufacturing LNPs, which enhance the targeted delivery of LNP-based RNA vaccines and therapeutic agents based on linear and / or circular mRNAs. The improved LNPs protect linear and / or circular mRNA payloads from degradation and clearance while enabling targeted systemic or local delivery for use as enhanced vaccines and / or therapeutic agents. Abstract

Claims

CLAIMS 1. A compound of Formula (CC): (CC), or a pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting of -OH, -OAc, -NR2, , , , , , , , , , , and ; each R is independently -H or C1-C6 aliphatic; X1is optionally substituted C2-C6 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, - NHC(O)- or -C(O)O-; X2is selected from the group consisting of a bond, -CH2- and -CH2CH2-; X2’is selected from the group consisting of a bond, -CH2- and -CH2CH2-; X3is selected from the group consisting of a bond, -CH2- and -CH2CH2-; X3’is selected from the group consisting of a bond, -CH2- and -CH2CH2-; X4and X5are independently optionally substituted C1-C10 aliphatic; Y1and Y2are independently selected from the group consisting of , , , , , , , or ; wherein the bond marked with an "*" is attached to X4or X5;R2is optionally substituted C1-C6aliphatic; R3is optionally substituted C1-C6aliphatic; R4is -CH(OR6)(OR7); -CH(SR6)(SR7); -CH(SR8)(SR9); -CH(R6)(R7); -R10; or optionally substituted C1-C14 aliphatic-R10wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, - S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; R5is -CH(OR8)(OR9); -CH(SR8)(SR9); -CH(R8)(R9); optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, - OC(O)-, -NHC(O)- or -C(O)O-; -R11; or optionally substituted C1-C14 aliphatic-R11, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, - NHC(O)- or -C(O)O-; R6and R7are each independently -R10; or optionally substituted -C1-C14aliphatic-R10; wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, - NHC(O)- or -C(O)O-; R8and R9are each independently -R11; optionally substituted -C1-C14 aliphatic wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or - C(O)O-; or optionally substituted -C1-C14aliphatic-R11wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; and each R10and R11are independently an optionally substituted bridged bicyclic or multicyclic C4-C12 cycloalkylenyl, or two R10or two R11taken together form an optionally substituted bridged bicyclic or multicyclic C4-C12cycloalkylenyl.

2. The compound of claim 1, wherein (CC-A), or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein the compound is of Formula (CC-B): (CC-B), or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein the compound is of Formula (CC-C): (CC-C), or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein the compound is of Formula (CC-D): (CC-D), or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein the compound is of Formula (CC-E): (CC-E), or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, wherein the compound is of Formula (CC-F):R4(CC-F), or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1, wherein the compound is of Formula (CC-F’):R4(CC-F’), or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1, wherein the compound is of Formula (CC-G):R4(CC-G), or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1, wherein the compound is of Formula (CC-H):(CC-H), or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1, wherein the compound is of Formula (CC-I):(CC-I), or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1, wherein the compound is of Formula (CC-J):(CC-J), or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1, wherein the compound is of Formula (CC-K):(CC-K), or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1, wherein the compound is of Formula (CC-L):(CC-L), or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1, wherein the compound is of Formula (CC-M):(CC-M), or a pharmaceutically acceptable salt thereof.

16. The compound of any of claims 1-9, 11-14, wherein R1is -OH or .

17. The compound of claim 16, wherein R1is -OH.

18. The compound of claim 16, wherein R1is .

19. The compound of claim 16, wherein R1is .

20. The compound of any of claims 1-19, wherein X1is optionally substituted C2-C6alkylene.

21. The compound of claim 20, wherein X1is optionally substituted C2-C4alkylene.

22. The compound of claim 20, wherein X1is selected from the group consisting of -(CH2)2-, -(CH2)3- and -(CH2)4-.

23. The compound of claim 22, wherein X1is -(CH2)2-.

24. The compound of claim 22, wherein X1is -(CH2)3-.

25. The compound of claim 22, wherein X1is -(CH2)4-.

26. The compound of any of claims 1-3, 6-12, or 15-25, wherein X4is optionally substituted C2-C7 aliphatic.

27. The compound of claim 26, wherein X4is optionally substituted C2-C3 alkylene.

28. The compound of claim 27, wherein X4is -(CH2)2-.

29. The compound of claim 27, wherein X4is -(CH2)3-.

30. The compound of any of claims 1-3, 6-12, or 15-29, wherein X5is optionally substituted C2-C7aliphatic.

31. The compound of claim 30, wherein X5is optionally substituted C2-C3alkylene.

32. The compound of claim 31, wherein X5is -(CH2)2-.

33. The compound of claim 31, wherein X5is -(CH2)3-.

34. The compound of any of claims 1-5, 11, or 16-33, wherein Y1is , wherein the bond marked with an "*" is attached to X4.

35. The compound of any of claims 1-5, 11, or 16-34, wherein Y2is , wherein the bond marked with an "*" is attached to X5.

36. The compound of any of claims 1-35, wherein R2is optionally substituted C1-C3 alkylene.

37. The compound of any of claims 1-35, wherein R2is optionally substituted C1 alkylene.

38. The compound of claim 37, wherein R2is –(CH2)-.

39. The compound of any of claims 1-35, wherein R3is optionally substituted C2alkylene.

40. The compound of claim 39, wherein R2is –(CH2)2-.

41. The compound of any of claims 1-40, wherein R3is optionally substituted C1-C3alkylene.

42. The compound of any of claims 1-41, wherein R3is optionally substituted C1alkylene.

43. The compound of claim 42, wherein R3is –(CH2)-.

44. The compound of any of claims 1-41, wherein R3is optionally substituted C2 alkylene.

45. The compound of claim 44, wherein R3is –(CH2)2-.

46. The compound of any of claims 1-10 or 16-45, R4is -CH(OR6)(OR7).

47. The compound of any of claims 1-10 or 16-45, R4is -CH(SR6)(SR7).

48. The compound of any of claims 1-10 or 16-45, R4is -R10.

49. The any of claims 1-10 or 16-45, R4is selected from the group consisting of51. The compound of any of claims 1-10 or 16-50, R5is -CH(OR6)(OR7).

52. The compound of any of claims 1-10 or 16-50, R5is -CH(OR8)(OR9).

53. The compound of any of claims 1-10 or 16-50, R5is -CH(SR6)(SR7).

54. The compound of any of claims 1-10 or 16-50, R5is -CH(OR8)(OR9).

55. The compound of any of claims 1-10 or 16-50, R5is -R11.O'56. The compound of any of claims 1-10 or 16-50, R5is selected from, , , , , , and .

57. The compound of any of claims 1-10 or 16-50, R5is selected from , , , and .

58. The compound of any of claims 1-55, wherein R6is -R10or optionally substituted -C1-C14aliphatic-R10.

59. The compound claim 58, wherein R6is optionally substituted -C1-C14 aliphatic-R10.

60. The compound claim 58, wherein R6is -CH2R10.

61. The compound claim 58, wherein R6is -R10.

62. The compound of any of claims 1-61, wherein R7is -R10or optionally substituted -C1-C14aliphatic-R10.

63. The compound claim 62, wherein R7is optionally substituted -C1-C14aliphatic-R10.

64. The compound claim 62, wherein R7is -CH2R10.

65. The compound claim 62, wherein R7is -R10.

66. The compound of any of claims 1-65, wherein R10is optionally substituted bridged bicyclic C5- C10 cycloalkylenyl.

67. The compound claim 66, wherein R10is an optionally substituted group selected from bicyclo[2.2.2]octyl or adamantyl.

68. The compound claim 66, wherein R10is selected from the group consisting of69. The compound of any of claims 1-68, wherein R8is optionally substituted -C1-C14 aliphatic.

70. The compound claim 69, wherein R8is optionally substituted -C7-C10 aliphatic.

71. The compound claim 69, wherein R8is selected from the group consisting of72. The compound of any of claims 1-71, wherein R9is optionally substituted -C1-C14 aliphatic.

73. The compound claim 72, wherein R9is optionally substituted -C7-C10 aliphatic.

74. The compound claim 72, wherein R9is selected from the group consisting of75. The compound of any of claims 1-74, wherein R11is optionally substituted bridged bicyclic C5- C10 cycloalkylenyl.

76. The compound claim 75, wherein R11is an optionally substituted group selected from bicyclo[2.2.2]octyl or adamantyl.

77. The compound claim 76, wherein R11is selected from the group consisting of78. A compound selected from the group consisting of those disclosed in Table (I-E) or a pharmaceutically acceptable salt therefore.

79. A pharmaceutical composition comprising: a) at least one lipid nanoparticle comprising at least one compound of any one of claims 1-78; and b) at least one nucleobase editing system.

80. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises a CRISPR-Cas gene editing system.

81. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises a prime editing system or components thereof.

82. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises a retron editing system.

83. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises a TnpB editing system.

84. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises an integrase editing system.

85. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises an integrase editing system.

86. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises an epigenetic editing system.

87. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises a gene writing system.

88. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises a gene inactivating system.

89. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises zinc finger nuclease.

90. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises aTALE Nuclease, a TALE nickase, Zinc Finger (ZF) Nuclease, ZF Nickase, mcganuclcasc, or a combination thereof.

91. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises a meganuclease.

92. The pharmaceutical composition of any one of claims 79-91, wherein the at least one lipid nanoparticle further comprises: i) at least one structural lipid; ii) at least one phospholipid; and iii) at least one PEGylated lipid.

93. The pharmaceutical composition of any one of claims 79-92, wherein the at least one structural lipid is selected from 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 any combinations thereof.

94. The pharmaceutical composition of any one of claims 79-93, wherein the at least one phospholipid is selected from l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl- sn-glycero-3-phosphoethanolamine (DOPE), l,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyLsn-glycero-phosphocholine (DMPC), 1.2-dioleoyl-sn-glycero-3- phosphocholine (DOPC), l,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2- diundecanoyl-sn-glycero-phosphocholine (DUPC), l-palmitoyl-2-oleoyl-sn-glycero-3- phosphocho line (POPC), l,2-di-O-octadcccnyl-sn-glyccro-3-phosphocholinc (18:0 Dicthcr PC), l-oleoyl-2-cholesterylhemisuc cinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl- sn-glycero-3-phosphocholine (C16 Lyso PC), l,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2- diarachidonoyl-sn-glycero-3-phosphocholine, l,2-didocosahexaenoyl-sn-glycero-3- phosphocholine, l,2-diphytanoylsn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2- distearoyl-sn-glycero-3-phosphoethanolamine, l,2-dilinoleoyl-sn-glycero-3- phosphoethanolamine, l,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl- sn-glycero-3-phosphoethanolamine, l,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, l,2-dioleoyl-sn-glycero-3-phospho-rac-(l -glycerol) sodium salt (DOPG), sodium (S)-2-ammonio- 3-((((R)-2-(oleoyloxy)-3-(stearoyloxy)propoxy)oxidophosphoryl)oxy)propanoate (L-a- phosphatidylserine; Brain PS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dioleoyl- phosphatidylethanolamine4-(N-maleimidomethyl)-cyclohexane-l -carboxylate (DOPE-mal), dioleoylphosphatidylglycerol (DOPG), L2-dioleoyl-sn-glycero-3-(phospho-L-serine) (DOPS),accll-fusogcnicphospholipid (DPhPE), dipalmitoylphosphatidylcthanolaminc (DPPE), 1,2- Dielaidoyl-sn-phosphatidylethanolamine (DEPE), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylcholine (DSPC), distearoyl- phosphatidy 1-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), l,2-dioleoyl-sn-glycero-3-phospho-(l’-myo-inositol) (DOPI; 18:1 PI), l,2-distearoyl-sn-glycero-3-phospho-L-serine (18:0 PS), l,2-dilinoleoyl-sn-glycero-3- phospho-L-serine (18:2 PS), l-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (16:0-18:1 PS; POPS), l-stearoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (18:0-18:1 PS), l-stearoyl-2-linoleoyl- sn-glycero-3-phospho-L-serine (18:0-18:2 PS), l-oleoyl-2-hydroxy-sn-glycero-3-phospho-L- serine (18:1 Lyso PS), l-stearoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:0 Lyso PS), and sphingomyelin.

95. The pharmaceutical composition of any one of claims 79-94, wherein the at least one PEGylated lipid is selected from (R)-2,3-bis(octadecyloxy)propyl-l- (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 Cl 4, 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-Cll, 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 CIO, N(Carbonyl-methoxypolyethylenglycol-2000)-l,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, l,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, C18PEG750, 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, l,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG2000, (R)-2,3-bis(octadecyloxy)propyl-l- (methoxypoly(ethyleneglycol)2000)propylcarbamate, (PEG)-C-DOMG, PEG-C-DMA, andDSPE-PEG-X.

96. The pharmaceutical composition of any one of claims 79-95, wherein the LNP further comprises at least one additional lipid component selected from l,2-di-O-octadecenyl-sn-glycero-3- phosphocholine (18:0 Diether PC), l,2-dilinolenoyl-sn-glycero-3-phosphocholine (18:3 PC), Acylcarnosine (AC), l-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), N-oleoyl- sphingomyelin (SPM) (C18:l), N-lignoceryl SPM (C24:0), N-nervonoylshphingomyelin (C24:l), Cardiolipin (CL), l,2-bis(tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine (DC8-9PC), dicetyl phosphate (DCP), dihexadecyl phosphate (DCP1), l,2-Dipalmitoylglycerol-3-hemisuccinate (DGSucc), short-chain bis-n-heptadecanoyl phosphatidylcholine (DHPC), dihexadecoyl- phosphoethanolamine (DHPE), 1 ,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2- dilauroyl-sn-glycero-3-PE (DLPE), dimyristoyl glycerol hemisuccinate (DMGS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (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-lrihydroxy-6-hydroxymethyl-letrahydro- pyran-2-ylsulfanyl)-propionamide (DOGP4aMan), dioleoylphosphatidylcholine (DOPC), dioleoylphosphatidylethanolamine (DOPE), dioleoyl-phosphatidylethanolamine4-(N- malcimidomcthyl) -cyclohexane- 1-carboxylatc (DOPE-mal), diolcoylphosphatidylglyccrol (DOPG), l,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), histaminedistearoylglycerol (HDSG), 1 ,2-Dipalmitoylglycerol-hemisuccinate-Na-Histidinyl- Hemisuccinate (HistSuccDG), N-(5'-hydroxy-3'-oxypentyl)-10-12-pentacosadiynamide (h-Pegi- PCDA), 2-[l-hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH), hydrogenatedsoybeanphosphatidylcholine (HSPC), 1,2-Dipalmitoylglycerol-O-a-histidinyl-Na- hemisuccinate (IsohistsuccDG), mannosialized dipalmitoylphosphatidylethanolamine (ManDOG), l,2-Dioleoyl-sn-Glycero-3-Phosphoethanolamine-N-[4-(p-maleimidomethyl)cyclohexane- carboxamide] (MCC-PE), l,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16:0 PE), 1- myristoyl-2-hydroxy-sn-glycero-phosphocholine (MHPC), a thiol-reactive maleimide headgroup lipid e.g.1 ,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N- [4-(p-maleimidophenyl)but-yramid (MPB-PE), Nervonic Acid (NA), sodium cholate (NaChol), l,2-dioleoyl-sn-glycero-3- [phosphoethanolamine-N-dodecanoyl (NC12-DOPE), l-oleoyl-2-cholesteryl hemisuccinoyl-sn- glycero-3-phosphocholine (OChemsPC), phosphatidylethanolamine lipid (PE), PE lipid conjugated with polyethylene glycol(PEG) (e.g., polyethylene glycol-distcaroylphosphatidylcthanolaminc lipid (PEG-PE)), phosphatidylglyccrol (PG), partially hydrogenated soy phosphatidylchloline (PIISPC), phosphatidylinositol lipid (PI), phosphotidylinositol-4-phosphate (PIP), palmitoyloleoylphosphatidylcholine (POPC), phosphatidylethanolamine (POPE), palmitoyloleyolphosphatidylglycerol (POPG), phosphatidylserine (PS), lissamine rhodamineB-phosphatidylethanolamine lipid (Rh-PE), purifiedsoy-derivedmixtureofphospholipids (SIOO), phosphatidylcholine (SM), 18-l-trans-PE,l- stearoyl-2-oleoyl-phosphatidyethanolamine (SOPE), soybean phosphatidylcholine (SPC), sphingomyelins (SPM), alpha, alpha-trehalose-6,6'-dibehenate (TDB), L2-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, l,2-diarachidonoyl-sn-glycero-3- phosphoethanolamine, l,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2- didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, l,2-dilinolenoyl-sn-glycero-3- phosphocholine, l,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero- 3-phosphoethanolamine, l,2-dioleyl-sn-glycero-3-phosphoethanolamine, 1,2-distearoyl-sn- glycero-3-phosphoethanolamine, 16-O-monomethyl PE, 16-O-dimethyl PE, and dioleylphosphatidylethanolamine.

97. A method of delivering a nuclcobasc editing system to a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any one of claims 79- 96.

98. The pharmaceutical composition of any one of claims 79-97 for use as a medicament.

99. Use of a pharmaceutical composition of any one of claims 79-97 for the manufacture of a medicament for delivery of a nucleobase editing system.

100. A lipid nanoparticle (LNP) comprising a compound of any one of claims 1-78, or a pharmaceutically acceptable salt thereof.

101. The LNP of claim 100, further comprising:(a) a PEG- lipid(b) a structural lipid; and(c) a non-ionizable lipid and / or a zwitterionic lipid.

102. The LNP of claim 101, wherein the lipid nanoparticle further comprises an additional ionizable lipid, besides a compound of Formula (CC).

103. The LNP of claim 101 or 102, wherein the PEG-lipid is selected from the group consisting ofPEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG-DMPE, PEG-DPPC, and PEG-DSPE.

104. The LNP of any one of claims 101-103, wherein the structural lipid is selected from the group consisting of cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, an alpha-tocopherol.

105. The LNP of any one of claims 101-104, wherein the non-ionizable lipid is a phospholipid selected from the group consisting of l,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-dioleoyLsn- glycero-3 -phosphocholine (DOPC), l,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2- diundecanoyl-sn-gly cero-phosphocholine (DUPC), 1 -palmitoy 1-2-oleoyl-sn-gly cero-3 - phosphocho line (POPC), l,2-di-O-octadcccnyl-sn-glyccro-3-phosphocholinc (18:0 Dicthcr PC), l-oleoyl-2-cholesterylhemisuc cinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl- sn-glycero-3-phosphocholine (C16 Lyso PC), l,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2- diarachidonoyl-sn-glycero-3-phosphocholine, l,2-didocosahexaenoyl-sn-glycero-3- phosphocholine, l,2-diphytanoylsn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2- distearoyl-sn-glycero-3-phosphoethanolamine, l,2-dilinoleoyl-sn-glycero-3- phosphoethanolamine, l,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl- sn-glycero-3-phosphoethanolamine, l,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, l,2-dioleoyl-sn-glycero-3-phospho-rac-(l -glycerol) sodium salt (DOPG), sodium (S)-2-ammonio- 3-((((R)-2-(oleoyloxy)-3-(stearoyloxy)propoxy)oxidophosphoryl)oxy)propanoate (L-a- phosphatidylserine; Brain PS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dioleoyl- phosphatidylethanolamine4-(N-maleimidomethyl)-cyclohexane-l -carboxylate (DOPE-mal), dioleoylphosphatidylglycerol (DOPG), l,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), l,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-(r -myo-inositol) (DOPI; 18:1 PI), l,2-distearoyl-sn-glycero-3-phospho-L- serine (18:0 PS), l,2-dilinoleoyl-sn-glycero-3-phospho-L-serine (18:2 PS), l-palmitoyl-2-oleoyl- sn-glycero-3-phospho-L-serine (16:0-18:1 PS; POPS), l-stearoyl-2-oleoyl-sn-glycero-3-phospho- L-serine (18:0-18:1 PS), l-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), l-stearoyl-2-hydroxy-sn-glyccro-3-phospho-L-scrinc (18:0 Lyso PS), and sphingomyelin.

106. The LNP of any one of claims 101-105, further comprising a targeting moiety.

107. The LNP of claim 106, wherein the targeting moiety is an antibody or a fragment thereof.

108. The LNP of any one of claims 101-107, further comprising an active agent.

109. The LNP of claim 108, wherein the active agent is a nucleic acid.1 10. The LNP of claim 109, wherein the nucleic acid is a ribonucleic acid.

111. The LNP of claim 110, 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 (IncRNA).

112. The LNP of claim 111, wherein the nucleic acid is a messenger RNA (mRNA) or a circular RNA.

113. The LNP of claim 112, wherein the mRNA includes an open reading frame encoding a cancer antigen.

114. The LNP of claim 112, wherein the mRNA includes an open reading frame encoding an immune checkpoint modulator.

115. The LNP of any one of claims 112-114, 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.

116. The LNP of claim 109, wherein the nucleic acid is suitable for a genome editing technique.

117. The LNP of claim 116, wherein the genome editing technique is clustered regularly interspaced short palindromic repeats (CRISPR) or transcription activator-like effector nuclease (TALEN).

118. The LNP of claim 109, 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.

119. The LNP of claim 112, wherein the mRNA is at least 30 nucleotides in length.

120. The LNP of claim 112, wherein the mRNA is at least 300 nucleotides in length.

121. A pharmaceutical composition comprising a LNP of any one of claims 101-120, and a pharmaceutically acceptable carrier.

122. The pharmaceutical composition of claim 121, formulated for intravenous or intramuscular administration.

123. The pharmaceutical composition of claim 121, which is formulated for intravenous administration.

124. A method for delivering a nucleic acid to a cell comprising contacting the cell with a LNP of any one of claims 101-120 or a pharmaceutical composition of any one of claims 99-101.

125. A method for treating a disease characterized by a deficiency 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 101-120, wherein the mRNA encodes the functional protein or a protein having the same biological activity as the functional protein.

126. 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 101-120 and a siRNA, wherein the siRNA targets expression of the overexpressed polypeptide.

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