EP-4734981-A1 - IONIZABLE LIPIDS AND LIPID NANOPARTICLE COMPOSITIONS FOR DELIVERY OF NUCLEIC ACIDS

EP4734981A1EP 4734981 A1EP4734981 A1EP 4734981A1EP-4734981-A1

Abstract

Disclosed herein are novel lipids that can be used in combination with other lipid components to form lipid nanoparticles for delivery of nucleic acid cargo. Also provided herein are pharmaceutical compositions comprising the novel lipid, or lipid nanoparticles comprising said novel lipids.

Inventors

MAJETI, BHARAT
ELSAYED, Mohamed, ElSayed Hamed

Assignees

RVAC Medicines (us) , Inc.

Dates

Publication Date: 20260506
Application Date: 20240701

Claims (1)

Attorney Docket No.41543-59274 (002WO) WHAT IS CLAIMED IS 1. A compound, wherein the compound is of formula I: (I) wherein: X is selected from -CH 2 -, -C(O)-, and -C(O)S-; Y is selected from C 1 -C 6 alkylene and C 1 -C 6 heteroalkylene; R 1 is selected from -(CH 2 ) n OC(O)Z 1 and -(CH 2 ) n C(O)OZ 1 , wherein Z 1 is C 6 -C 20 alkyl or C 6 - C 20 alkenyl, and n is an integer from 1-10; R 2 is selected from -(CH 2 ) m OC(O)Z 2 , -(CH 2 ) m C(O)OZ 2 , and C 10 -C 20 alkyl, wherein Z 2 is C 6 - C 20 alkyl or C 6 -C 20 alkenyl, and m is an integer from 0-10; R 3 is selected from H and C 1 -C 6 alkyl; R 4 is selected from H and OH; R 5 is C 1 -C 6 alkyl, optionally substituted with one or more groups selected from -OH, -OR’, - SH, -SR’, -SCOR’, -NH 2 , -NHR’, -N(R’) 2 , -NHCOR’, NR’COR’, -CO 2 H, -CO 2 R’, -COR’, -CONH 2 , - CONHR’, -CON(R’) 2 , -COSH, -COSR’, wherein R’ is C 1-6 alkyl or C 3-10 cycloalkyl; R 6 is C 1 -C 6 alkyl, optionally substituted with one or more groups selected from -OH, -OR’, - SH, -SR’, -SCOR’, -NH 2 , -NHR’, -N(R’) 2 , -NHCOR’, NR’COR’, -CO 2 H, -CO 2 R’, -COR’, -CONH 2 , - CONHR’, -CON(R’) 2 , -COSH, -COSR’, wherein R’ is C 1-6 alkyl or C 3-10 cycloalkyl; or R 5 and R 6 together form a C 2 -C 9 heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, and optionally substituted C 1 -C 6 heterocyclyl-C 1 -C 4 alkyl; or is a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein one or more of the following is true: (a) R 1 is -(CH 2 ) n OC(O)Z 1 , wherein Z 1 is C 6 -C 20 alkenyl; (b) R 2 is -(CH 2 ) m OC(O)Z 2 , wherein Z 2 is C 6 -C 20 alkenyl; (c) R 2 is -(CH 2 ) m OC(O)Z 2 , wherein Z 2 is C 6 -C 20 alkyl; Attorney Docket No.41543-59274 (002WO) (d) R 2 is C 10 -C 20 alkyl; (e) R 4 is OH; (f) R 2 is -(CH 2 ) m C(O)OZ 2 , wherein Z 2 is C 6 -C 20 alkenyl; (g) R 1 is -(CH2)nOC(O)Z 1 , wherein Z 1 is C6-C20 alkyl; (h) R 2 is C 10 -C 20 alkyl and R 4 is H; (i) R 1 is -(CH2)nC(O)OZ 1 ; or (j) R 2 is -(CH 2 ) m C(O)OZ 2 . 3. The compound of claim 2, wherein R 1 is -(CH 2 ) n OC(O)Z 1 , wherein Z 1 is C 6 -C 20 alkenyl. 4. The compound of claim 2, wherein R 2 is -(CH 2 ) m OC(O)Z 2 . 5. The compound of claim 4, wherein Z 2 is C 6 -C 20 alkenyl. 6. The compound of claim 4, wherein Z 2 is C 6 -C 20 alkyl. 7. The compound of claim 2, wherein R 2 is C 10 -C 20 alkyl. 8. The compound of claim 2 or 7, wherein R 4 is OH. 9. The compound of claim 2, wherein R 2 is -(CH 2 ) m C(O)OZ 2 , wherein Z 2 is C 6 -C 20 alkenyl. 10. The compound of claim 2, wherein R 1 is -(CH 2 ) n OC(O)Z 1 , wherein Z 1 is C 6 -C 20 alkyl. 11. The compound of claim 10, wherein R 2 is C 10 -C 20 alkyl and R 4 is H. 12. The compound of claim 2, wherein R 1 is -(CH 2 ) n C(O)OZ 1 . 13. The compound of claim 12, wherein R 2 is -(CH 2 ) m C(O)OZ 2 . 14. The compound of any one of claims 1-13, wherein R 3 is H. 15. The compound of any one of claims 1-13, wherein R 3 is C 1 -C 6 alkyl. 16. The compound of claim 1, wherein the compound is of formula Ia: Attorney Docket No.41543-59274 (002WO) wherein: Z 1 and Z 2 are each C 6 -C 20 alkenyl; n is an integer from 1 to 10; and m is an integer from 1 to 10. 17. The compound of claim 16, wherein one or both of Z 1 and Z 2 have at least two double bonds. 18. The compound of claim 16 or 17, wherein Z 1 and Z 2 are the same. 19. The compound of any one of claims 16-18, wherein Z 1 and Z 2 are -(CH 2 ) 7 CH=CHCH 2 CH=CH(CH 2 ) 4 CH 3 . 20. The compound of any one of claims 16-19, wherein n is 2. 21. The compound of any one of claims 16-20, wherein m is 1. 22. The compound of any one of claims 16-21, wherein the compound is selected from: Compound Structure d . 23. , Attorney Docket No.41543-59274 (002WO) wherein: Z 1 is C 6 -C 20 alkenyl; n is an integer from 1 to 10; and R 2 is C 10 -C 20 alkyl. 24. The compound of claim 23, wherein Z 1 has at least two double bonds. 25. The compound of claim 23 or 24, wherein Z 1 is -(CH 2 ) 7 CH=CHCH 2 CH=CH(CH 2 ) 4 CH 3 . 26. The compound of any one of claims 23-25, wherein n is 2. 27. The compound of any one of claims 23-26, wherein the compound is selected from: Compound Structure 2 d . 28. wherein: Z 1 is C6-C20 alkenyl; Attorney Docket No.41543-59274 (002WO) n is an integer from 1 to 10; m is an integer from 1 to 10; and R 7 and R 8 are each C 4 -C 20 alkyl. 29. The compound of claim 28, wherein Z 1 has at least two double bonds. 30. The compound of claim 28 or 29, wherein Z 1 is -(CH 2 ) 7 CH=CHCH 2 CH=CH(CH 2 ) 4 CH 3 . 31. The compound of any one of claims 28-30, wherein n is 2. The compound of any one of claims 28-31, wherein R 7 and R 8 are each C 4 -C 10 alkyl. 33. The compound of any one of claims 28-32, wherein m is 5. 34. The compound of any one of claims 28-33, wherein the compound is selected from: Compound Structure 3 35. , Attorney Docket No.41543-59274 (002WO) wherein: n is an integer from 1 to 10; R 2 is C 10 -C 20 alkyl; and R 7 and R 8 are each C 4 -C 20 alkyl. 36. The compound of claim 35, wherein R 7 and R 8 are each C 4 -C 10 alkyl. 37. The compound of claim 35 or 36, wherein m is 6. 38. The compound of any one of claims 35-37, wherein the compound is selected from: Compound Structure 4 3 wherein: Z 1 is C 6 -C 20 alkenyl; n is an integer from 1 to 10; m is an integer from 1 to 10; and Attorney Docket No.41543-59274 (002WO) R 7 is C 4 -C 20 alkyl. 40. The compound of claim 39, wherein Z 1 has at least two double bonds. 41. The compound of claim 39 or 40, wherein Z 1 is -(CH 2 ) 7 CH=CHCH 2 CH=CH(CH 2 ) 4 CH 3 . 42. The compound of any one of claims 39-41, wherein n is 3. 43. The compound of any one of claims 39-42, wherein R 7 is C 4 -C 10 alkyl. 44. The compound of any one of claims 39-43, wherein m is 5. 45. The compound of any one of claims 39-44, wherein the compound is selected from: Compound Structure 7 d . wherein: Z 1 and Z 2 are each C 6 -C 20 alkenyl; n is an integer from 1 to 10; m is an integer from 0 to 10; and Attorney Docket No.41543-59274 (002WO) R 3 is C 1 -C 6 alkyl. 47. The compound of claim 46, wherein one or both of Z 1 and Z 2 have at least two double bonds. 48. The compound of claim 46 or 47, wherein Z 1 and Z 2 are the same. 49. The compound of any one of claims 46-48, wherein Z 1 and Z 2 are -(CH 2 ) 7 CH=CHCH 2 CH=CH(CH 2 ) 4 CH 3 . 50. The compound of any one of claims 46-49, wherein n is 1. 51. The compound of any one of claims 46-50, wherein m is 0. 52. The compound of any one of claims 46-51, wherein R 3 is methyl. 53. The compound of any one of claims 46-52, wherein the compound is selected from: Compound Structure 8 . 5 wherein: Z 1 and Z 2 are each branched C 6 -C 20 alkyl; Attorney Docket No.41543-59274 (002WO) n is an integer from 1 to 10; and m is an integer from 0 to 10. 55. The compound of claim 54, wherein Z 1 and Z 2 are the same. 56. The compound of claim 54 or 55, wherein Z 1 and Z 2 are each , wherein p is an integer from 3-8. 57. The compound of any one of claims 54-56, wherein n is 3. 58. The compound of any one of claims 54-57, wherein m is 2. 59. The compound of any one of claims 54-58, wherein the compound is: . 60. The compound of , C 6 alkylene. The compound of claim 60, wherein -NH-X-Y-NR 5 R 6 is the following: , wherein o is an integer from 1 to 5. 62. The compound of claim 60 or 61, wherein R 5 and R 6 are C 1 -C 6 alkyl. 63. The compound of claim 62, wherein R 5 and R 6 are methyl. 64. The compound of claim 60 or 61, wherein R 5 is C 1 -C 6 alkyl and R 6 is hydroxy-C 1 -C 6 alkyl. 65. The compound of claim 64, wherein R 5 is methyl and R 6 is -CH 2 CH 2 OH. Attorney Docket No.41543-59274 (002WO) 66. The compound of claim 60 or 61, wherein R 5 and R 6 together form a C 2 -C 9 heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with - OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, and optionally substituted C 1 -C 6 heterocyclyl-C 1 -C 4 alkyl. 67. The compound of claim 66, wherein -NH-X-Y-NR 5 R 6 is the following: , wherein A is selected from CHR 9 , O, selected from H, OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, and optionally substituted C 1 -C 6 heterocyclyl-C 1 -C 4 alkyl. 68. The compound of claim 67, wherein A is CHR 9 and R 9 is OH. 69. The compound of claim 67, wherein A is CHR 9 and R 9 is C 1 -C 6 alkyl. 70. The compound of claim 67, wherein A is CHR 9 and R 9 is methyl. 71. The compound of claim 67, wherein A is CHR 9 and R 9 is -CH 2 OH. 72. The compound of claim 67, wherein A is CHR 9 and R 9 is -CH 2 CH 2 OH. 73. The compound of claim 67, wherein A is S. 74. The compound of claim 67, wherein A is O. 75. The compound of claim 67, wherein A is NR 9 and R 9 is C 1 -C 6 alkyl. 76. The compound of claim 67, wherein A is NR 9 and R 9 is hydroxy-C 1 -C 6 alkyl. 77. The compound of claim 67, wherein A is NR 9 and R 9 is -CH 2 CH 2 OCH 2 CH 2 OH. 78. The compound of claim 67, wherein A is NR 9 and R 9 is . Attorney Docket No.41543-59274 (002WO) 79. The compound of claim 67, wherein A is NR 9 and R 9 is . 80. The compound of claim 66, wherein the following: , wherein R 10 and R 11 are each and hydroxy-C 1 -C 6 alkyl. 81. The compound of claim 80, wherein R 10 and R 11 are each H. 82. The compound of claim 80, wherein R 10 and R 11 are each OH. 83. The compound of claim 80, wherein R 10 and R 11 are each hydroxy-C 1 -C 6 alkyl. 84. The compound of claim 80, wherein R 10 is H and R 11 is OH. 85. The compound of any one of claims 1-59, wherein X is -C(O)- and Y is C 1 -C 6 heteroalkylene. 86. The compound of claim 85, wherein -NH-X-Y-NR 5 R 6 has the following structure: , wherein: Q is selected from S and O; and o is an integer from 1 to 4. 87. The compound of claim 85 or 86, wherein R 5 and R 6 are C 1 -C 6 alkyl. 88. The compound of claim 87, wherein R 5 and R 6 are methyl. 89. The compound of claim 85 or 86, wherein R 5 is C 1 -C 6 alkyl and R 6 is hydroxy-C 1 -C 6 alkyl. 90. The compound of claim 89, wherein R 5 is methyl and R 6 is -CH 2 CH 2 OH. Attorney Docket No.41543-59274 (002WO) 91. The compound of claim 85 or 86, wherein R 5 and R 6 together form a C 2 -C 9 heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with - OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, and optionally substituted C 1 -C 6 heterocyclyl-C 1 -C 4 alkyl. 92. The compound of claim 91, wherein -NH-X-Y-NR 5 R 6 is the following: , wherein: A is selected from selected from H, OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, and optionally substituted C 1 -C 6 heterocyclyl-C 1 -C 4 alkyl. 93. The compound of clam 92, wherein A is CHR 9 and R 9 is OH. 94. The compound of clam 92, wherein A is CHR 9 and R 9 is C 1 -C 6 alkyl. 95. The compound of claim 92, wherein A is CHR 9 and R 9 is methyl. 96. The compound of claim 92, wherein A is CHR 9 and R 9 is -CH 2 CH 2 OH. 97. The compound of claim 92, wherein A is S. 98. The compound of claim 92, wherein A is O. 99. The compound of claim 92, wherein A is NR 9 and R 9 is C 1 -C 6 alkyl. 100. The compound of claim 92, wherein A is NR 9 and R 9 is hydroxy-C 1 -C 6 alkyl. 101. The compound of claim 92, wherein A is NR 9 and R 9 is -CH 2 CH 2 OCH 2 CH 2 OH. 102. The compound of claim 92, wherein A is NR 9 and R 9 is . Attorney Docket No.41543-59274 (002WO) 103. The compound of claim 91, wherein -NH-X-Y-NR 5 R 6 is the following: , wherein R 10 and R 11 are each hydroxy-C 1 -C 6 alkyl. 104. The compound of claim 103, wherein R 10 and R 11 are each H. 105. The compound of claim 103, wherein R 10 and R 11 are each OH. 106. The compound of claim 103, wherein R 10 and R 11 are each hydroxy-C 1 -C 6 alkyl. 107. The compound of claim 103, wherein R 10 is H and R 11 is OH. 108. The compound of any one of claims 1-59, wherein X is -C(O)S- and Y is C 1 -C 6 alkylene. 109. The compound of claim 108, wherein -NH-X-Y-NR 5 R 6 is the following: , wherein o is an integer from 1 to 6. 110. The compound of claim 108 or 109, wherein R 5 and R 6 are C 1 -C 6 alkyl. 111. The compound of claim 108 or 109, wherein R 5 and R 6 are methyl. 112. The compound of claim 108 or 109, wherein R 5 is C 1 -C 6 alkyl and R 6 is hydroxy-C 1 -C 6 alkyl. 113. The compound of claim 108 or 109, wherein R 5 is methyl and R 6 is -CH 2 CH 2 OH. 114. The compound of claim 108 or 109, wherein R 5 and R 6 together form a C 2 -C 9 heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, and optionally substituted C 1 -C 6 heterocyclyl-C 1 -C 4 alkyl. Attorney Docket No.41543-59274 (002WO) 115. The compound of claim 114, wherein -NH-X-Y-NR 5 R 6 is the following: , wherein A is selected from CHR 9 , is selected from H, OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, and optionally substituted C 1 -C 6 heterocyclyl-C 1 -C 4 alkyl. 116. The compound of claim 115, wherein A is CHR 9 and R 9 is OH. 117. The compound of claim 115, wherein A is CHR 9 and R 9 is C 1 -C 6 alkyl. 118. The compound of claim 115, wherein A is CHR 9 and R 9 is methyl. 119. The compound of claim 115, wherein A is CHR 9 and R 9 is -CH 2 OH. 120. The compound of claim 115, wherein A is CHR 9 and R 9 is -CH 2 CH 2 OH. 121. The compound of claim 115, wherein A is S. 122. The compound of claim 115, wherein A is O. 123. The compound of claim 115, wherein A is NR 9 and R 9 is C 1 -C 6 alkyl. 124. The compound of claim 115, wherein A is NR 9 and R 9 is hydroxy-C 1 -C 6 alkyl. 125. The compound of claim 115, wherein A is NR 9 and R 9 is -CH 2 CH 2 OCH 2 CH 2 OH. 126. The compound of claim 115, wherein A is NR 9 and R 9 is . 127. The compound of claim 115, R 9 is . Attorney Docket No.41543-59274 (002WO) 128. The compound of claim 115, wherein -NH-X-Y-NR 5 R 6 is the following: , wherein R 10 and R 11 are each and hydroxy-C 1 -C 6 alkyl. 129. The compound of claim 128, wherein R 10 and R 11 are each H. 130. The compound of claim 128, wherein R 10 and R 11 are each OH. 131. The compound of claim 128, wherein R 10 and R 11 are each hydroxy-C 1 -C 6 alkyl. 132. The compound of claim 128, wherein R 10 is H and R 11 is OH. 133. The compound of any one of claims 1-59, wherein X is -CH 2 - and Y is C 1 -C 6 alkylene. 134. The compound of claim 133, wherein -NH-X-Y-NR 5 R 6 has the following structure: , wherein o is an integer from 0 to 5. 135. The compound of claim 133 or 134, wherein R 5 and R 6 are C 1 -C 6 alkyl. 136. The compound of claim 133 or 134, wherein R 5 and R 6 are methyl. 137. The compound of claim 133 or 134, wherein R 5 is C 1 -C 6 alkyl and R 6 is hydroxy-C 1 -C 6 alkyl. 138. The compound of claim 133 or 134, wherein R 5 is methyl and R 6 is -CH 2 CH 2 OH. 139. The compound of claim 133 or 134, wherein R 5 and R 6 together form a C 2 -C 9 heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, and optionally substituted C 1 -C 6 heterocyclyl-C 1 -C 4 alkyl. 140. The compound of claim 139, wherein -NH-X-Y-NR 5 R 6 is the following: , Attorney Docket No.41543-59274 (002WO) wherein A is selected from CHR 9 , O, S, and NR 9 , wherein R 9 is selected from H, OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, and optionally substituted C 1 -C 6 heterocyclyl-C 1 -C 4 alkyl. 141. The compound of claim 140, wherein A is CHR 9 and R 9 is OH. 142. The compound of claim 140, wherein A is CHR 9 and R 9 is C 1 -C 6 alkyl. 143. The compound of claim 140, wherein A is CHR 9 and R 9 is methyl. 144. The compound of claim 140, wherein A is CHR 9 and R 9 is -CH 2 OH. 145. The compound of claim 140, wherein A is CHR 9 and R 9 is -CH 2 CH 2 OH. 146. The compound of claim 140, wherein A is S. 147. The compound of claim 140, wherein A is O. 148. The compound of claim 140, wherein A is NR 9 and R 9 is C 1 -C 6 alkyl. 149. The compound of claim 140, wherein A is NR 9 and R 9 is hydroxy-C 1 -C 6 alkyl. 150. The compound of claim 140, wherein A is NR 9 and R 9 is -CH 2 CH 2 OCH 2 CH 2 OH. 151. The compound of claim 140, wherein A is NR 9 and R 9 is . 152. The compound of claim 140, R 9 is . 153. The compound of claim 140, is the following: , 1 0 1 wherein R and R 1 are each H, and hydroxy-C 1 -C 6 alkyl. Attorney Docket No.41543-59274 (002WO) 154. The compound of claim 153, wherein R 10 and R 11 are each H. 155. The compound of claim 153, wherein R 10 and R 11 are each hydroxy-C 1 -C 6 alkyl. 156. The compound of claim 153, wherein R 10 is H and R 11 is OH. 157. A pharmaceutical composition comprising a compound of any one of claims 1-156 and one or more pharmaceutically acceptable excipient. 158. The pharmaceutical composition of claim 157, wherein the compound is in a lipid nanoparticle. 159. The pharmaceutical composition of claim 158, wherein the lipid nanoparticle further comprises one or more lipids selected from one or more ionizable lipids, one or more cationic lipids, one or more structural lipids, one or more conjugated lipids, and one more helper lipids. 160. The pharmaceutical composition of claim 158 or 159, wherein the lipid nanoparticle comprises a nucleic acid. 161. The pharmaceutical composition of claim 160, wherein the lipid nanoparticle encapsulates the nucleic acid. 162. The pharmaceutical composition of claim 160 or 161, wherein the nucleic acid is RNA. 163. The pharmaceutical composition of claim 162, wherein the RNA is selected from siRNA, antisense RNA, single stranded RNA, microRNA, mRNA, noncoding RNA, multivalent RNA, and circular RNA.

Description

Attorney Docket No.41543-59274 (002WO) IONIZABLE LIPIDS AND LIPID NANOPARTICLE COMPOSITIONS FOR DELIVERY OF NUCLEIC ACIDS BACKGROUND [1] The effective targeted delivery of nucleic acids represents a continuing medical challenge. In particular, the delivery of nucleic acids to cells is made difficult by their relative instability and low cell permeability. [2] Lipid-containing nanoparticles (lipid nanoparticles or LNPs), liposomes, and lipoplexes have proven effective as transport vehicles into cells and/or intracellular compartments for nucleic acids. LNPs typically contain four or more components, e.g., ionizable lipid(s), cationic lipid(s), helper lipid(s), structural lipid(s), and conjugated lipid(s) (also known as PEGylated lipids), among which the ionizable lipid plays a major role in protecting RNAs and facilitating their cytosolic transport. Ionizable lipids are positively charged at acidic pH to condense RNAs into LNPs but are neutral at physiological pH to minimize toxicity. They can be protonated in the acidic endosome after cellular uptake and interact with anionic endosomal phospholipids to form cone-shaped ion pairs that are not compatible with a bilayer. These cationic-anionic lipid pairs drive the transition from the bilayer structure to the inverted hexagonal HII phase, which facilitates membrane fusion/disruption, endosomal escape and cargo release into the cytosol. [3] Though a variety of such LNPs have been demonstrated, improvements in safety, efficacy, and specificity are still lacking. There remains a need in the art for improved therapeutic nucleic acid compositions that are suitable for general therapeutic use. Preferably, these compositions would encapsulate nucleic acids with high efficiency, have high drug:lipid ratios, protect the encapsulated nucleic acid from degradation and clearance in serum, be suitable for systemic delivery, and provide intracellular delivery of the encapsulated nucleic acid. In addition, these LNPs should be well- tolerated and provide an adequate therapeutic index, such that patient treatment at an effective dose of the nucleic acid is not associated with significant toxicity and/or risk to the patient. The present disclosure provides such compositions and methods of using the compositions to introduce nucleic acids into cells, including for the treatment of diseases. SUMMARY [4] The present disclosure provides ionizable lipids and related LNPs, compositions, and methods. The LNPs can be used to encapsulate therapeutic nucleic acid cargo. Pharmaceutical compositions comprising such LNPs are also provided. [5] In one aspect, ionizable lipids are provided herein, wherein the ionizable lipid is a compound of formula (I): Attorney Docket No.41543-59274 (002WO) (I) wherein: X is selected from -CH2-, -C(O)-, Y is selected from C1-C6 alkylene and C1-C6 heteroalkylene; R1 is selected from -(CH2)nOC(O)Z1 and -(CH2)nC(O)OZ1, wherein Z1 is C6-C20 alkyl or C6-C20 alkenyl, and n is an integer from 1-10; R2 is selected from -(CH2)mOC(O)Z2, -(CH2)mC(O)OZ2, and C10-C20 alkyl, wherein Z2 is C6-C20 alkyl or C6-C20 alkenyl, and m is an integer from 0-10; R3 is selected from H and C1-C6 alkyl; R4 is selected from H and OH; R5 is C1-C6 alkyl, optionally substituted with one or more groups selected from -OH, -OR’, -SH, -SR’, -SCOR’, -NH2, -NHR’, -N(R’)2, -NHCOR’, NR’COR’, -CO2H, -CO2R’, -COR’, -CONH2, - CONHR’, -CON(R’)2, -COSH, -COSR’, wherein R’ is C1-6 alkyl or C3-10 cycloalkyl; R6 is C1-C6 alkyl, optionally substituted with one or more groups selected from -OH, -OR’, -SH, -SR’, -SCOR’, -NH2, -NHR’, -N(R’)2, -NHCOR’, NR’COR’, -CO2H, -CO2R’, -COR’, -CONH2, - CONHR’, -CON(R’)2, -COSH, -COSR’, wherein R’ is C1-6 alkyl or C3-10 cycloalkyl; or R5 and R6 together form a C2-C9 heterocycle with the nitrogen atom to which they are attached, wherein the heterocycle is optionally substituted with -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, and optionally substituted C1-C6 heterocyclyl-C1-C4 alkyl; or is a pharmaceutically acceptable salt thereof. [6] In another aspect, the present disclosure provides a LNP comprising one or more compounds of formula I and, optionally, one or more additional ionizable lipid, one or more cationic lipid, one or more structural lipid, one or more conjugated lipid, and one or more helper lipid. The LNP encapsulates nucleic acid cargo (i.e., polynucleotides). Nucleic acid compositions of any structure may be included in the LNPs, e.g., a mRNA, a siRNA, a shRNA, a guide RNA (gRNA), a microRNA (miRNA), or a circular RNA (circRNA). [7] In another aspect, the present disclosure provides compositions (e.g., pharmaceutical compositions) comprising one or more compounds of formula I and one or more pharmaceutically acceptable excipients. [8] In another aspect, the present disclosure provides compositions (e.g., pharmaceutical compositions) comprising a plurality of LNPs and one or more pharmaceutically acceptable excipie