Pegylated lipid nanoparticles modified with cell penetrating peptides for delivery of nucleic acids

Abstract

The present disclosure provides compositions of lipid nanoparticles including lipid components and a cell-penetrating peptide conjugated to the lipid components useful for the delivery of nucleic acids including mRNAs, and methods thereof. These compositions may be used to treat a disease or disorder for which the delivery of a nucleic acid is therapeutically effective.

Description

Atty Docket 5635-0102W01PEGYLATED LIPID NANOPARTICLES MODIFIED WITH CELL PENETRATING PEPTIDES FOR DELIVERY OF NUCLEIC ACIDSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Application Ser. No. 63 / 765,151, entitled “Pegylated Lipid Nanoparticles Modified with Cell Penetrating Peptides for Delivery of Nucleic Acids,” filed on 28 February 2025. This application is incorporated herein by reference in its entirety.TECHNICAL FIELD

[0002] The present disclosure provides lipid nanoparticles (LNPs) that are useful for stabilizing and delivering cargo molecules such as nucleic acids, and related methods.REFERENCE TO SEQUENCE LISTING

[0003] This application contains a Sequence Listing in electronic format. The Sequence Listing file, entitled 5635-102WOl.xml, was created on 27 February 2026, and is 8,192 bytes in size. The information in electronic format of the Sequence Listing is incorporated herein by reference in its entirety.BACKGROUND

[0004] RNA and gene therapy therapeutics have emerged as a promising new class of medicine, holding great potential to treat a broad array of diseases. For example, US 2020 / 0129445 to ModernaTx describes LNP compositions that include an ionizable lipid, a phospholipid, and a sterol or tocopherol.

[0005] US 2021 / 0121411 to the University of Texas describes LNP compositions that include a cationic ionizable lipid, a phospholipid, a PEGylated lipid, and a steroid.

[0006] US 2024 / 0002331 to Tidal Therapeutics describes LNP compositions that include LNPs decorated with antigen-targeting nanobodies.

[0007] US 2021 / 0244665 to University of Tennessee Research Foundation describes processes for preparing neutral liposomes.

[0008] Nucleic acids can be vulnerable to enzymatic degradation and it is known that lipids can exasperate the underlying disease and abate efficacy in severe disease models (Wu et al., 2014, Tousignant et al., 2000 and Lv et al., 2006). Thus, there is a need in the field of nucleic acid therapeutics to develop safer and more effective delivery systems that can efficiently package, protect, and deliver cargo molecules such as nucleic acids to diseased cells and tissues.Atty Docket 5635-0102W01SUMMARY OF THE INVENTION

[0009] The present invention is directed to lipid nanoparticle (LNP) formulation comprising (i) at least one phospholipid; (ii) at least one sterol; (iii) a PEG-lipid; and (iv) a lipopeptide comprising a cell-penetrating peptide and methods of using the LNP for delivering cargo molecules to a cell. The LNP may be used as a therapeutic agent delivery system, in which the therapeutic agent includes nucleic acids or other small molecules.

[0010] In one aspect, the present invention is directed to lipopeptides and methods for the preparation, manufacture and therapeutic use thereof. In some aspects, the lipopeptide is selected from the group consisting of LL-1 -24001, LL-1-24002, LL-1 -24003, LL-1 -24004, LL-1-24005, LL-1-24006, LL-1-24007, LL-1-24008, LL-1-24009, LL-1-24010, LL-1-24011, LL-1-24012, LL-1-24013, LL-1-24014, LL-1-24015, LL-1-24016, LL-1-24017, LL-1-24018, LL-1-24019, LL-1-24020, LL-1-24021, LL-1-24022, LL-1-24023, LL-1-24024, LL-1-24025, LL-1-24026, LL-1-24027, LL-1-24028, LL-1-24029, LL-1-24030, LL-1-24031, LL-1-24032, LL-1-24033, LL-1-24034, LL-1-24035, LL-1-24036, LL-1-24037, LL-1-24038, LL-1-24039, LL-1-24040, LL-1 -24041, LL-1 -24042, LL-1 -24043, LL-1 -24044, LL-1 -24045, LL-1 -24046, LL-1-24047. LL-1 -24048, LL-1 -24049, LL-1 -24050, LL-1 -24051, LL-1 -24052, LL-1 -24053, LL-1-24054, LL-1-24055, LL-1-24056, LL-1-24057, LL-1-24058, LL-1-24059, LL-1-24060, LL-1-24061, LL-1-24062, LL-1-24063, LL-1-24064, LL-1-24065, LL-1-24066, LL-1-24067, LL-1-24068, LL-1-24069, LL-1-24070, LL-1-24071, LL-1-24072, LL-1-24073, LL-1-24074, LL-1-24075, LL-1 -24076, LL-1 -24077, LL-1 -24078, LL-1 -24079, LL-1 -24080, LL-1 -24081, LL-1-24082, LL-1-24083, LL-1-24084, LL-1-24085, LL-1-24086, LL-1-24087, LL-1-24088, LL-1-24089, LL-1-24090, LL-1-24091, LL-1-24092, LL-1-24093, LL-1-24094, LL-1-24095, LL-1-24096, LL-1-24097, LL-1-24098, LL-1-24099, LL-1-24100, LL-1-24101, LL-1-24102, LL-1-24103, LL-1-24104, LL-1-24105, LL-1-24106, LL-1-24107, LL-1-24108, LL-1-24109, LL-1-24110, LL-1-24111, LL-1-24112, LL-1-24113, LL-1-24114, LL-1-24115, LL-1-24116, LL-1-24117, LL-1-24118, LL-1-24119, LL-1-24120, LL-1-24121, LL-1-24122, LL-1-24123, LL-1-24124, LL-1-24125, LL-1-24126, LL-1-24127, LL-1-24128, LL-1-24129, LL-1-24130, LL-1-24131, LL-1-24132, LL-1-24133, LL-1-24134, LL-1-24135, LL-1-24136, LL-1-24137, LL-1-24138, LL-1-24139, LL-1-24140, LL-1-24141, LL-1-24142, LL-1-24143, LL-1-24144, LL-1-24145, LL-1-24146, LL-1-24147, LL-1-24148, LL-1-24149, LL-1-24150, LL-1-24151, LL-1-24152, LL-1-24153, LL-1-24154, LL-1-24155, LL-1-24156, LL-1-24157, LL-1-24158, LL-1-24159, LL-1-24160, LL-1-24161, LL-1-24162, LL-1-24163, LL-1-24164, LL-1-24165, LL-1-24166, LL-1-24167, LL-1-24168, LL-1-24169, LL-1-24170, LL-1-24171, LL-1-24172, LL-Atty Docket 5635-0102WG11-24173, LL-1-24174, LL-1-24175, LL-1-24176, LL-1-24177, LL-1-24178, LL-1-24179, LL-1-24180, LL-1-24181, LL-1-24182, LL-1-24183, LL-1-24184, LL-1-24185, LL-1-24186, LL-1-24187, LL-1-24188, LL-1-24189, LL-1-24190, LL-1-24191, LL-1-24192, LL-1-24193, LL-1-24194, LL-1-24195, LL-1-24196, LL-1-24197, LL-1-24198, LL-1-24199, LL-1-24200, LL-1-24201, LL-1-24202, LL-1-24203, LL-1-24204, LL-1-24205, LL-1-24206, LL-1-24207, LL-1-24208, LL-1-24209, LL-1-24210, LL-1-24211, LL-1-24212, LL-1-24213, LL-1-24214, LL-1-24215. LL- 1-24216, LL- 1-24217, LL- 1-24218, LL- 1-24219, LL- 1-24220, LL- 1-24221, LL-1-24222, LL-1-24223, LL-1-24224, LL-1-24225, LL-1-24226, LL-1-24227, LL-1-24228, LL-1-24229, LL-1-24230, LL-1-24231, LL-1-24232, LL-1-24233, LL-1-24234, LL-1-24235, LL-1-24236, LL-1-24237, LL-1-24238, LL-1-24239, LL-1-24240, LL-1-24241, LL-1-24242, LL-1-24243, LL-1-24244, LL-1-24245, LL-1-24246, LL-1-24247, LL-1-24248, LL-1-24249, and LL- 1-24250. In some aspects, the lipopeptides of the disclosure

[0011] Each of the aspects of the present disclosure can encompass various elements of the present disclosure. It is, therefore, anticipated that each of the aspects of the present disclosure involving any one element or combinations of elements can be included in each aspect of the present disclosure. This disclosure is not limited in its application to the details of construction and the arrangement of components set forth in the following detailed description or illustrated in the drawings.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG. 1 shows (R8)-(amide)-(dipalmitoleoyl-PE).

[0013] FIG. 2 shows (R8)-(amide)-(dipalmitoyl-PE).

[0014] FIG. 3 shows (R8)-(amide)-(palmitoleic acid).

[0015] FIG. 4 shows (R8)-(ester)-(dilinoleoyl-PG).

[0016] FIG. 5 shows (R8)-(ester)-(dipalmitoleoyl-PE).

[0017] FIG. 6 shows (R9)-(amide)-(dipalmitoleoyl-PE).

[0018] FIG. 7 shows (R9)-(amide)-(palmitoleic acid).

[0019] FIG. 8 shows (R9)-(ester)-(dilinoleoyl-PG).

[0020] FIG. 9 shows (R9)-(ester)-(dipalmitoleoyl-PE).

[0021] FIG. 10 shows (R10)-(amide)-(oleic acid).

[0022] FIG. 11 shows (R10)-(amide)-(palmitoleic acid).

[0023] FIG. 12 shows (R10)-(ester)-(palmitoleic acid).

[0024] FIG. 13 shows (Rll)-(amide)-(palmitoleic acid).

[0025] FIG. 14 shows (R12)-(amide)-(palmitoleic acid).Atty Docket 5635-0102WG1

[0026] FIG. 15 shows LL-1-24001.

[0027] FIG. 16 shows LL- 1-24002.

[0028] FIG. 17 shows LL-1-24003.

[0029] FIG. 18 shows LL- 1 -24004.

[0030] FIG. 19 shows LL- 1-24005.

[0031] FIG. 20 shows LL- 1-24006.

[0032] FIG. 21 shows LL- 1-24007.

[0033] FIG. 22 shows LL-1-24008.

[0034] FIG. 23 shows LL- 1-24009.

[0035] FIG. 24 shows LL-1-24010.

[0036] FIG. 25 shows LL- 1-24011.

[0037] FIG. 26 shows LL- 1-24012.

[0038] FIG. 27 shows LL- 1-24013.

[0039] FIG. 28 shows LL-1-24014.

[0040] FIG. 29 shows LL-1-24015.

[0041] FIG. 30 shows LL-1-24016.

[0042] FIG. 31 shows LL-1-24017.

[0043] FIG. 32 shows LL-1-24018.

[0044] FIG. 33 shows LL- 1-24019.

[0045] FIG. 34 shows LL- 1-24020.

[0046] FIG. 35 shows LL-1-24021.

[0047] FIG. 36 shows LL- 1-24022.

[0048] FIG. 37 shows LL-1-24023.

[0049] FIG. 38 shows LL- 1-24024.

[0050] FIG. 39 shows LL-1-24025.

[0051] FIG. 40 shows LL- 1 -24026.

[0052] FIG. 41 shows LL- 1-24027.

[0053] FIG. 42 shows LL-1-24028.

[0054] FIG. 43 shows LL- 1 -24029.

[0055] FIG. 44 shows LL-1-24030.

[0056] FIG. 45 shows LL- 1-24031.

[0057] FIG. 46 shows LL-1-24032.

[0058] FIG. 47 shows LL-1-24033.Atty Docket 5635-0102WG1

[0059] FIG. 48 shows LL-1-24034.

[0060] FIG. 49 shows LL- 1-24035.

[0061] FIG. 50 shows LL- 1-24036.

[0062] FIG. 51 shows LL- 1-24037.

[0063] FIG. 52 shows LL-1-24038.

[0064] FIG. 53 shows LL-1-24039.

[0065] FIG. 54 shows LL-1-24040.

[0066] FIG. 55 shows LL- 1-24041.

[0067] FIG. 56 shows LL- 1-24042.

[0068] FIG. 57 shows LL-1-24043.

[0069] FIG. 58 shows LL- 1 -24044.

[0070] FIG. 59 shows LL- 1 -24045.

[0071] FIG. 60 shows LL- 1 -24046.

[0072] FIG. 61 shows LL-1-24047.

[0073] FIG. 62 shows LL-1-24048.

[0074] FIG. 63 shows LL- 1-24049.

[0075] FIG. 64 shows LL- 1-24050.

[0076] FIG. 65 shows LL- 1 -24051.

[0077] FIG. 66 shows LL-1-24052.

[0078] FIG. 67 shows LL-1-24053.

[0079] FIG. 68 shows LL- 1-24054.

[0080] FIG. 69 shows LL- 1-24055.

[0081] FIG. 70 shows LL-1-24056.

[0082] FIG. 71 shows LL-1-24057.

[0083] FIG. 72 shows LL-1-24058.

[0084] FIG. 73 shows LL- 1-24059.

[0085] FIG. 74 shows LL-1-24060.

[0086] FIG. 75 shows LL-1-24061.

[0087] FIG. 76 shows LL- 1-24062.

[0088] FIG. 77 shows LL-1-24063.

[0089] FIG. 78 shows LL- 1-24064.

[0090] FIG. 79 shows LL-1-24065.

[0091] FIG. 80 shows LL- 1 -24066.Atty Docket 5635-0102WG1

[0092] FIG. 81 shows LL-1-24067.

[0093] FIG. 82 shows LL-1-24068.

[0094] FIG. 83 shows LL- 1 -24069.

[0095] FIG. 84 shows LL- 1-24070.

[0096] FIG. 85 shows LL- 1-24071.

[0097] FIG. 86 shows LL-1-24072.

[0098] FIG. 87 shows LL-1-24073.

[0099] FIG. 88 shows LL- 1-24074.[000100] FIG. 89 shows LL-1-24075.[000101] FIG. 90 shows LL-1-24076.[000102] FIG. 91 shows LL-1-24077.[000103] FIG. 92 shows LL- 1-24078.[000104] FIG. 93 shows LL- 1-24179.[000105] FIG. 94 shows LL-1-24180.[000106] FIG. 95 shows LL-1-24181.[000107] FIG. 96 shows LL-1-24182.[000108] FIG. 97 shows LL-1-24083.[000109] FIG. 98 shows LL- 1-24084.[000110] FIG. 99 shows LL-1-24085.[000111] FIG. 100 shows LL- 1-24086 [000112] FIG. 101 shows LL- 1-24087 [000113] FIG. 102 shows LL- 1-24088 [000114] FIG. 103 shows LL- 1-24089 [000115] FIG. 104 shows LL- 1-24090 [000116] FIG. 105 shows LL- 1-24191 [000117] FIG. 106 shows LL- 1-24192 [000118] FIG. 107 shows LL- 1-24193 [000119] FIG. 108 shows LL- 1-24194 [000120] FIG. 109 shows LL- 1-24195 [000121] FIG. 110 shows LL-1-24196 [000122] FIG. Ill shows LL-1-24197 [000123] FIG. 112 shows LL-1-24198 [000124] FIG. 113 shows LL-1-24199Atty Docket 5635-0102WG1[000125] FIG. 114 shows LL-1-24200.[000126] FIG. 115 shows LL- 1-24201.[000127] FIG. 116 shows LL-1-24202.[000128] FIG. 117 shows LL-1-24203.[000129] FIG. 118 shows LL-1-24204.[000130] FIG. 119 shows LL- 1-24205.[000131] FIG. 120 shows LL- 1-24206.[000132] FIG. 121 shows LL- 1-24207.[000133] FIG. 122 shows LL- 1-24208.[000134] FIG. 123 shows LL- 1-24209.[000135] FIG. 124 shows LL- 1-24210.[000136] FIG. 125 shows LL- 1-24211.[000137] FIG. 126 shows LL- 1-24212.[000138] FIG. 127 shows LL-1 -24213.[000139] FIG. 128 shows LL-1 -24214.[000140] FIG. 129 shows LL-1 -24215.[000141] FIG. 130 shows LL-1 -24216.[000142] FIG. 131 shows LL-1 -24217.[000143] FIG. 132 shows LL-1-24218.[000144] FIG. 133 shows LL-1-24219.[000145] FIG. 134 shows LL-1-24220.[000146] FIG. 135 shows LL-1-24221.[000147] FIG. 136 shows LL-1 -24222.[000148] FIG. 137 shows LL-1-24223.[000149] FIG. 138 shows LL-1 -24224.[000150] FIG. 139 shows LL-1-24225.[000151] FIG. 140 shows LL-1 -24226.[000152] FIG. 141 shows LL-1 -24227.[000153] FIG. 142 shows LL-1 -24228.[000154] FIG. 143 shows LL-1 -24229.[000155] FIG. 144 shows LL-1 -24230.[000156] FIG. 145 shows LL-1 -24231.[000157] FIG. 146 shows LL-1 -24232.Atty Docket 5635-0102WG1[000158] FIG. 147 shows LL-1-24233.[000159] FIG. 148 shows LL- 1-24234.[000160] FIG. 149 shows LL-1-24235.[000161] FIG. 150 shows LL-1-24236 [000162] FIG. 151 shows LL- 1-24237.[000163] FIG. 152 shows LL- 1-24238.[000164] FIG. 153 shows LL- 1-24239.[000165] FIG. 154 shows LL- 1-24240.[000166] FIG. 155 shows LL-1-24241.[000167] FIG. 156 shows LL- 1-24242.[000168] FIG. 157 shows LL- 1-24243.[000169] FIG. 158 shows LL- 1-24244.[000170] FIG. 159 shows LL- 1-24245.[000171] FIG. 160 shows LL- 1-24246.[000172] FIG. 161 shows LL- 1-24247.[000173] FIG. 162 shows LL- 1-24248.[000174] FIG. 163 shows LL-1-24249.[000175] FIG. 164 shows LL- 1-24250.[000176] FIG. 165 shows LL- 1-24091.[000177] FIG. 166 shows LL- 1-24092.[000178] FIG. 167 shows LL- 1-24093.[000179] FIG. 168 shows LL- 1-24094.[000180] FIG. 169 shows LL- 1-24095.[000181] FIG. 170 shows LL- 1-24096.[000182] FIG. 171 shows LL- 1-24097.[000183] FIG. 172 shows LL-1-24098.[000184] FIG. 173 shows LL- 1-24099.[000185] FIG. 174 shows LL-1-24100.[000186] FIG. 175 shows LL- 1-24101.[000187] FIG. 176 shows LL- 1-24102.[000188] FIG. 177 shows LL- 1-24103.[000189] FIG. 178 shows LL-1-24104.[000190] FIG. 179 shows LL- 1-24105.Atty Docket 5635-0102WG1[000191] FIG. 180 shows LL-1-24106.[000192] FIG. 181 shows LL-1-24107.[000193] FIG. 182 shows LL-1-24108.[000194] FIG. 183 shows LL-1-24109.[000195] FIG. 184 shows LL-1-24110.[000196] FIG. 185 shows LL-1-24111.[000197] FIG. 186 shows LL-1-24112.[000198] FIG. 187 shows LL-1-24113.[000199] FIG. 188 shows LL-1-24114.[000200] FIG. 189 shows LL-1-24115.[000201] FIG. 190 shows LL-1-24116.[000202] FIG. 191 shows LL-1-24117.[000203] FIG. 192 shows LL-1-24118.[000204] FIG. 193 shows LL-1-24119.[000205] FIG. 194 shows LL-1-24120.[000206] FIG. 195 shows LL-1-24121.[000207] FIG. 196 shows LL-1-24122.[000208] FIG. 1 7 shows LL-1-24123.[000209] FIG. 198 shows LL-1-24124.[000210] FIG. 199 shows LL-1-24125.[000211] FIG. 200 shows LL-1-24126.[000212] FIG. 201 shows LL-1-24127.[000213] FIG. 202 shows LL-1-24128.[000214] FIG. 203 shows LL-1-24129.[000215] FIG. 204 shows LL-1-24130.[000216] FIG. 205 shows LL- 1-24131.[000217] FIG. 206 shows LL-1-24132.[000218] FIG. 207 shows LL-1-24133.[000219] FIG. 208 shows LL-1-24134.[000220] FIG. 209 shows LL-1-24135.[000221] FIG. 210 shows LL-1-24136.[000222] FIG. 211 shows LL-1-24137.[000223] FIG. 212 shows LL-1-24138.Atty Docket 5635-0102WG1[000224] FIG. 213 shows LL- 1-24139.[000225] FIG. 214 shows LL-1-24140.[000226] FIG. 215 shows LL- 1-24141.[000227] FIG. 216 shows LL-1 -24142.[000228] FIG. 217 shows LL-1-24143.[000229] FIG. 218 shows LL-1-24144.[000230] FIG. 219 shows LL-1-24145.[000231] FIG. 220 shows LL-1 -24146.[000232] FIG. 221 shows LL-1-24147.[000233] FIG. 222 shows LL-1-24148.[000234] FIG. 223 shows LL-1-24149.[000235] FIG. 224 shows LL-1 -24150.[000236] FIG. 225 shows LL-1 -24151.[000237] FIG. 226 shows LL-1-24152.[000238] FIG. 227 shows LL-1 -24153.[000239] FIG. 228 shows LL-1 -24154.[000240] FIG. 229 shows LL-1-24155.[000241] FIG. 230 shows LL-1-24156.[000242] FIG. 231 shows LL-1-24157.[000243] FIG. 232 shows LL-1 -24158.[000244] FIG. 233 shows LL-1 -24159.[000245] FIG. 234 shows LL-1 -24160.[000246] FIG. 235 shows LL-1 -24161.[000247] FIG. 236 shows LL-1 -24162.[000248] FIG. 237 shows LL-1 -24163.[000249] FIG. 238 shows LL-1 -24164.[000250] FIG. 239 shows LL-1-24165.[000251] FIG. 240 shows LL-1 -24166.[000252] FIG. 241 shows LL- 1 -24167.[000253] FIG. 242 shows LL-1-24168.[000254] FIG. 243 shows LL-1 -24169.[000255] FIG. 244 shows LL-1-24170.[000256] FIG. 245 shows LL-1 -24171.Atty Docket 5635-0102WG1[000257] FIG. 246 shows LL-1-24172.[000258] FIG. 247 shows LL- 1-24173.[000259] FIG. 248 shows LL-1-24174.[000260] FIG. 249 shows LL-1-24175.[000261] FIG. 250 shows LL- 1-24176.[000262] FIG. 251 shows LL-1-24177.[000263] FIG. 252 shows LL-1-24178.[000264] FIG. 253 shows LL- 1-24179.[000265] FIG. 254 shows LL- 1-24180.[000266] FIG. 255 shows LL-1 -24181.[000267] FIG. 256 shows LL-1 -24182.[000268] FIG. 257 shows LL-1 -24183.[000269] FIG. 258 shows LL-1-24184.[000270] FIG. 259 shows LL-1-24185.[000271] FIG. 260 shows LL-1 -24186.[000272] FIG. 261 shows LL-1 -24187.[000273] FIG. 262 shows LL-1-24188.[000274] FIG. 263 shows LL-1 -24189.[000275] FIG. 264 shows LL-1 -24190.[000276] FIG. 265 shows LL-1 -24079.[000277] FIG. 266 shows LL-1 -24080.[000278] FIG. 267 shows LL-1-24081.[000279] FIG. 268 shows LL-1-24082.[000280] FIG. 269 shows LL-1 -24083.[000281] FIG. 270 shows LL-1-24084.[000282] FIG. 271 shows LL-1 -24085.[000283] FIG. 272 shows LL-1 -24086.[000284] FIG. 273 shows LL-1-24087.[000285] FIG. 274 shows LL-1 -24088.[000286] FIG. 275 shows LL-1 -24089.[000287] FIG. 276 shows an exemplary process for making the lipid nanoparticle of the disclosure.Atty Docket 5635-0102W01[000288] Note that any one of more of the illustrative components of the molecule are optional and the present disclosure includes aspects that contain fewer than all of the illustrated elements.DETAILED DESCRIPTION[000289] The disclosure relates to compositions of multi-functional lipid nanoparticles, lipopeptides and methods for the preparation, manufacture and therapeutic use thereof.[000290] Although the present disclosure is described in detail below, it is to be understood that this disclosure is not limited to the particular methodologies, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to limit the scope of the present disclosure. Unless defined otherwise, all percentages, ratios and proportions herein are by weight. All temperatures are in degrees Celsius (°C) unless otherwise specified. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.Definitions[000291] As used herein, “biologically active agent” refers to any agent that, when administered to a subject, has a therapeutic, diagnostic, and / or prophylactic effect and / or elicits a biological and / or pharmacological effect. Therapeutic agents are also referred to as “actives” or “active agents.” Such agents include, but are not limited to, cytotoxins, radioactive ions, chemotherapeutic agents, small molecule drugs, proteins, and nucleic acids.[000292] As used herein, a “patient” or “subject” is an individual to which a composition or formulation of the present disclosure may be administered, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes.[000293] As used herein, “therapeutically effective amount” means an amount of an agent to be delivered (e.g., nucleic acid, drug, composition, therapeutic agent, diagnostic agent, prophylactic agent, etc.) that is sufficient — when administered to a subject suffering from or susceptible to an infection, disease, disorder, and / or condition — to treat, improve symptoms of, diagnose, prevent, and / or delay the onset of the infection, disease, disorder, and / or condition. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage FormsAtty Docket 5635-0102W01(vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); and Pickar, Dosage Calculations (1999)).[000294] As used herein, “delivering” means providing an entity to a destination. For example, delivering a biologically active agent to a subject may involve administering an LNP including the biologically active agent to the subject (e.g., by an intravenous, intramuscular, intradermal, or subcutaneous route). Administration of an LNP to a subject or cell may involve contacting one or more cells with the LNP.[000295] As used herein “payload” as used herein refers to compounds enclosed within the LNPs. For example, a biological active ingredient is a payload that can be delivered in vivo or in vitro. This term is used interchangeably with the terms “biologically active agent”, “cargo”, or “cargo molecule”.[000296] As used herein, a “nanoparticle composition” or an “LNP” is a composition comprising one or more lipids. LNPs typically have diameters micrometers or smaller and may include a lipid bilayer. LNPs encompass, for example, liposomes (e.g., lipid vesicles) and lipoplexes.[000297] As used herein, “linker” refers to a moiety connecting two moieties, for example, the connection between a lipid and a peptide. A linker may include one or more groups including but not limited to phosphate groups (e.g., phosphates, boranophosphates, thiophosphates, selenophosphates, and phosphonates), alkyl groups, amidates, glycerols, amides or esters, or thiol ethers. For example, a peptide may be linked to a lipid in the N-terminal to C-terminal direction by a thiol ether.[000298] As used herein, “mutant” and “variant” are interchangeable and refer to a molecule (polypeptide or nucleic acid) exhibiting one or more sequence modifications with respect to the native or wildtype counterpart. Any modification(s) can be envisaged, including substitution, insertion, and / or deletion of one or more nucleotide / amino acid residue(s).[000299] As used herein, “in vitro” refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, in a Petri dish, etc., rather than within an organism (e.g., animal, plant, or microbe).[000300] As used herein, “in vivo” refers to events that occur within an organism (e.g., animal, plant, or microbe).[000301] As used herein, “in situ” refers to events that occur in its original place, or in its natural context.Atty Docket 5635-0102W01[000302] As used herein “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and / or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.[000303] As used herein, “compound,” is meant to include all isomers and isotopes of the structure depicted. “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. Further, a compound, salt, or complex of the present disclosure can be prepared in combination with solvent or water molecules to form solvates and hydrates by routine methods.Lipid Nanoparticle (LNP)[000304] The present disclosure provides lipid nanoparticles comprising distinct lipid components. These distinct lipid components are (i) at least one phospholipid; (ii) at least one sterol; (iii) a PEG-lipid; and (iv) a lipopeptide comprising a cationic cell-penetrating peptide. In some aspects, the lipopeptide further comprises a linker and a lipid.[000305] Suitable — but non-limiting — processes for assembling the LNPs of the present disclosure are described in US 2021 / 0244665, the contents of which are herein incorporated by reference in their entirety. A sample process flow for LNP assembly is shown in FIG. 165.[000306] In some aspects, the LNP formulation comprises about 10-50 mol-% phospholipid, about 20-50 mol-% sterol, about 1-10 mol-% PEG-lipid, and about 1-20 mol-% lipopeptide. In some aspects, the lipopeptide comprises a peptide, a linker and a lipid according to the formula (peptide)-(linkerj-(lipid) in the N-terminal to C-terminal direction. In some aspects, the peptide is an oligoarginine, a homoarginine, or a combination of any one or more of these. In some aspects, the oligoarginine consists of 2-50 arginine residues, for example 8-12 arginine residues or 8 arginine residues (R8). In some aspects, the oligoarginine lipopeptide comprises SEQ ID NO: 2. In some aspects, the linker is an amide or an ester. In some aspects, the ester is thiol ether. In some aspects, the amide is CONH2. N-succinyl, N-glutaryl, or N-dodecanoyl. In some aspects, the linker is a cleavable linker. In some aspects, the lipid is one or more ionizable lipids.[000307] In one aspect, the lipid component of the lipopeptide is one or more fatty acids. In some aspects, the one or more fatty acids is a heptadecan-9-yl, a 2,2-dimethylpropanoyl, a 1,2-Atty Docket 5635-0102W01dioleoyl, an ionisable aminolipid, a Dlin, a didodecyl, a stearic fatty acid, a caprylic acid, a capric acid, a lauric acid, a mystristic acid, a palmitic acid, a steraric acid, a palmitoletic acid, an oleic acid, a linoleic acid, a linolenic acid, an a-eleostearic acid, a ricinoletic acid, a vemolic acid, a eicosatetraenoic acid, eicosapentaenoic acid, a di-DHA-PE, a docosahexaenoic acid (DHA), a alpha-eleostreayl fatty acid, a 1 ,2-dipalmitoleoyl-PE, a 1,2-dilinoleoyl PE, a 1,2-dilinoleoyl PG, a di-arachidonoyl PE, a di-arachidonoyl PG, a 1,2-dipalmitoyl-sn-Glycero, a 18:1 1,2-dioleoyl-sn-glycero, or a combination thereof.[000308] In one aspect, the lipopeptide of the LNP formulation of the disclosure comprises a peptide, a linker, and a lipid according to the formula (R8)-(amide)-(dipalmitoleoyl-PE), (R8)-(amide)-(dipalmitoyl-PE), (R8)-(amide)-(palmitoleic acid), (R8)-(ester)-(dilinoleoyl-PG), (R8)-(ester)-(dipalmitoleoyl-PE), (R9)-(amide)-(dipalmitoleoyl-PE), (R9)-(amide)-(palmitoleic acid), (R9)-(ester)-(dilinoleoyl-PG), (R9)-(ester)-(dipalmitoleoyl-PE), (R10)-(amide)-(oleic acid), (R10)-(amide)-(palmitoleic acid), (R10)-(ester)-(palmitoleic acid), (R11)-(amide)-(palmitoleic acid), or (R12)-(amide)-(palmitoleic acid).[000309] In one aspect, the lipopeptide of the LNP formulation of the disclosure comprises a lipopeptide selected from the group LL- 1-24001, LL- 1-24002, LL- 1-24003, LL- 1-24004, LL-1-24005, LL-1-24006, LL-1-24007, LL-1-24008, LL-1-24009, LL-1-24010, LL-1-24011, LL-1-24012, LL-1-24013, LL-1-24014, LL-1-24015, LL-1-24016, LL-1-24017, LL-1-24018, LL-1-24019, LL-1-24020, LL-1-24021, LL-1-24022, LL-1-24023, LL-1-24024, LL-1-24025, LL-1-24026, LL-1-24027, LL-1-24028, LL-1-24029, LL-1-24030, LL-1-24031, LL-1-24032, LL-1-24033, LL-1-24034, LL-1-24035, LL-1-24036, LL-1-24037, LL-1-24038, LL-1-24039, LL-1-24040, LL-1-24041, LL-1-24042, LL-1-24043, LL-1-24044, LL-1-24045, LL-1-24046, LL-1-24047, LL-1-24048, LL-1-24049, LL-1-24050, LL-1-24051, LL-1-24052, LL-1-24053, LL-1-24054, LL-1-24055, LL-1-24056, LL-1-24057, LL-1-24058, LL-1-24059, LL-1-24060, LL-1-24061, LL- 1-24062, LL- 1-24063, LL- 1-24064, LL- 1-24065, LL- 1-24066, LL- 1-24067, LL-1-24068, LL-1-24069, LL-1-24070, LL-1-24071, LL-1-24072, LL-1-24073, LL-1-24074, LL-1-24075, LL-1-24076, LL-1-24077, LL-1-24078, LL-1-24079, LL-1-24080, LL-1-24081, LL-1-24082, LL-1-24083, LL-1-24084, LL-1-24085, LL-1-24086, LL-1-24087, LL-1-24088, LL-1-24089, LL- 1-24090, LL- 1-24091, LL- 1-24092, LL- 1-24093, LL- 1-24094, LL- 1-24095, LL-1-24096, LL-1-24097, LL-1-24098, LL-1-24099, LL-1-24100, LL-1-24101, LL-1-24102, LL-1-24103, LL-1-24104, LL-1-24105, LL-1-24106, LL-1-24107, LL-1-24108, LL-1-24109, LL-1-24110, LL-1-24111, LL-1-24112, LL-1-24113, LL-1-24114, LL-1-24115, LL-1-24116, LL-1-24117, LL- 1-24118, LL- 1-24119, LL- 1-24120, LL-1-24121, LL-1-24122, LL- 1-24123, LL-Atty Docket 5635-0102W011-24124, LL-1-24125, LL-1-24126, LL-1-24127, LL-1-24128, LL-1-24129, LL-1-24130, LL- 1-24131, LL-1-24132, LL-1-24133, LL-1-24134, LL-1-24135, LL-1-24136, LL-1-24137, LL-1-24138, LL-1-24139, LL-1-24140, LL-1-24141, LL-1-24142, LL-1-24143, LL-1-24144, LL-1-24145, LL-1-24146, LL-1-24147, LL-1-24148, LL-1-24149, LL-1-24150, LL-1-24151, LL-1-24152, LL-1-24153, LL-1-24154, LL-1-24155, LL-1-24156, LL-1-24157, LL-1-24158, LL-1-24159, LL-1-24160, LL-1-24161, LL-1-24162, LL-1-24163, LL-1-24164, LL-1-24165, LL- 1-24166, LL-1-24167, LL-1-24168, LL-1-24169, LL-1-24170, LL-1-24171, LL-1-24172, LL-1-24173, LL-1-24174, LL-1-24175, LL-1-24176, LL-1-24177, LL-1-24178, LL-1-24179, LL-1-24180, LL-1-24181, LL-1-24182, LL-1-24183, LL-1-24184, LL-1-24185, LL-1-24186, LL-1-24187, LL-1-24188, LL-1-24189, LL-1-24190, LL-1-24191, LL-1-24192, LL-1-24193, LL- 1-24194, LL-1-24195, LL-1-24196, LL-1-24197, LL-1-24198, LL-1-24199, LL-1-24200, LL-1-24201, LL- 1-24202, LL- 1-24203, LL- 1-24204, LL- 1-24205, LL- 1-24206, LL- 1-24207, LL-1-24208, LL-1-24209, LL-1-24210, LL-1-24211, LL-1-24212, LL-1-24213, LL-1-24214, LL-1-24215, LL-1-24216, LL-1-24217, LL-1-24218, LL-1-24219, LL-1-24220, LL-1-24221, LL-1-24222, LL- 1-24223, LL- 1-24224, LL- 1-24225, LL- 1-24226, LL- 1-24227, LL- 1-24228, LL- 1-24229. LL-1-24230, LL-1-24231, LL-1-24232, LL-1-24233, LL-1-24234, LL-1-24235, LL-1-24236, LL-1-24237, LL-1-24238, LL-1-24239, LL-1-24240, LL-1-24241, LL-1-24242, LL-1-24243, LL-1-24244, LL-1-24245, LL-1-24246, LL-1-24247, LL-1-24248, LL-1-24249, LL-1-24250, or a combination thereof. Table 1 lists a non-limiting variety of example lipopeptides for use in the NPLs disclosed herein.Table 1. Example LipopeptidesAtty Docket 5635-0102W01Atty Docket 5635-0102W01Atty Docket 5635-0102W01Atty Docket 5635-0102W01Atty Docket 5635-0102W01[000310] In one aspect, the LNP formulation of the disclosure encapsulates a therapeutic, diagnostic, and / or prophylactic agent. In some aspects, the therapeutic, diagnostic, and / or prophylactic agent is a nucleic acid. In some aspects, the nucleic acid is an RNA or DNA molecule. In some aspects, the nucleic acid is an RNA molecule. In some aspects, the nucleic acid is a DNA molecule. In some aspects, the DNA is a double stranded DNA (dsDNA). In some aspects, the DNA is a single stranded DNA (ssDNA). In some aspects, the nucleic acid is a linear nucleic acid molecule. In some aspects, the nucleic acid is a circular nucleic acid molecule. In some aspects, the RNA is a circRNA, an siRNA, an miRNA, an shRNA, a tRNA, or an mRNA. In some aspects, the RNA is an mRNA.Atty Docket 5635-0102W01Phospholipid[000311] The lipid component of an LNP composition may include one or more phospholipids. As used herein, “phospholipid” refers to a lipid that includes a phosphate moiety and one or more carbon chains, such as unsaturated fatty acid chains. A phospholipid may include one or more multiple (e.g., double or triple) bonds (e.g., one or more unsaturations). Particular phospholipids may facilitate fusion to a membrane. Fusion of a phospholipid to a membrane may allow one or more elements of a lipid-containing composition to pass through the membrane permitting, e.g., delivery of the one or more elements to a cell. Phospholipids useful in the compositions and methods of the present disclosure may be selected from the following non-limiting group: l,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), l,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), l,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1 ,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), l-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), l,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), l-oleoyl-2-cholesterylhemisuccinoyl-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-phospho-choline, l,2-diphytanoyl-sn-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, l,2-diarachidonoyl-sn-glycero-3-phospho-ethanolamine, l,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(l -glycerol) sodium salt (DOPG), or sphingomyelin.Sterol[000312] The lipid component of an LNP may include one or more sterols. As used herein “sterol” or “sterol derivative” refer to a class of compounds with a four ring, 17 carbon, cyclic structure which can further comprises one or more substitutions. A sterol derivative comprises any molecule having the 4-member ring structure characteristic of steroids and a hydroxyl ( — OH) or ester ( — OR) substitution at the 3 -carbon position, for example, having the exemplary structure below:Atty Docket 5635-0102WG1[000313] The skilled artisan will understand that a sterol derivative can be further substituted at one or more of the other ring carbons, for example, with one or more non-alkyl substitutions, including alkyl groups, alkoxy groups, hydroxy groups, oxo groups, acyl groups, or a double bond between two or more carbon atoms:[000314] In certain embodiments, a sterol for use in the compositions and methods of the present disclosure may be selected from the following non-limiting group: cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, tomatine, ursolic acid, and alpha-tocopherol.PEG-Lipids[000315] The lipid component of an LNP composition may include one or more lipids modified with polyethylene glycol (“PEG-lipids”). Such species may be alternately referred to as PEGylated lipids. As used herein “polyethylene glycol-conjugated lipid’’ or “PEG-lipid” refer to any lipid to which a PEG group has been attached. For example, a PEG lipid may be selected from the following non-limiting group: PEG-modified phosphatidylethanolamines, PEG-modified phosphatidic acids, PEG-modified ceramides, PEG-modified dialkylamines, PEG-modified diacylglycerols, PEG-modified di alkylglycerols, 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.[000316] In some aspects, the PEG-lipid is PEG-modified phosphatidylethanolamines, PEG-modified phosphatidic acids, PEG-modified ceramides, PEG-modified dialkylamines, PEG-modified diacylglycerols, PEG-modified dialkylglycerols, or a combination thereof.LipopeptideAtty Docket 5635-0102W01[000317] The present disclosure provides lipopeptides. In some aspects, the present disclosure provides LNPs comprising a lipopeptide component. In some aspects, the lipopeptide component is a lipopeptide of the disclosure.[000318] The lipid component of an LNP may include one or more lipopeptides. As used herein, “lipopeptide” refers to a molecule that comprises a lipid-like moiety covalently linked to a peptide moiety.[000319] The lipopeptide can contribute any amount from 1 mol-% to 20 mol-% of the mass of the LNPs disclosed herein. By way of non-limiting example, the lipopeptide may contribute 1.5 mol-%, 2.0 mol-%, 2.5 mol-%, 3.0 mol-%, 3.5 mol-%, 4.0 mol-%, 4.5 mol-%, 5.0 mol-%, 7.5 mol-%, 10 mol-%, 12 mol-%, 15 mol-%, 17 mol-%, or 19 mol-% of the mass of the LNPs.[000320] In some aspects, the lipopeptide comprises a peptide, a linker and a lipid according to the formula of any of the species disclosed in Table 1.[000321] The lipopeptides of the disclosure can be synthesized by: performing solid phase peptide synthesis; followed by performing solid phase lipopeptide synthesis; and followed by separation of the lipopeptide from the solid phase.[000322] In one aspect, the solid phase peptide synthesis begins with the attachment of a first carboxylic acid containing molecule having no free amines to a solid phase in the presence of activating chemicals (e.g., hydroxybenzotriazole, l-hydroxy-7-azabenzotriazole, and ethyl cyanohydroxyiminoacetate). The molecule attached to a solid phase iswhere K is a solid phase, “linker” is an amide or an ester, Fmoc is a fluorenylmethoxycarbonyl protecting group, R is an amino acid side chain, Y is a side chain protecting group, and X is O or NH.[000323] The resin is then washed before a second carboxylic acid containing molecule having no free amines is attached in the presence of activating chemicals to the N terminus of the first carboxylic acid having no free amines. The resin is then washed again. These iterations of washing and attachment in the presence of activating chemicals is repeated until the desired peptide has been synthesized.[000324] The ultimate result of this iterative process isAtty Docket 5635-0102W01K - Linker - Xwhere m is the number of iterations of wash / attach steps. This iterative process will yield a polypeptide that is “m” amino acid residues in length.[000325] In some aspects, the solid phase is a resin. In some aspects, the amino acid side chain is independently selected from the side chains of alanine, isoleucine, leucine, methionine, valine, proline, glycine, aspartic acid, glutamic acid, arginine, histidine, lysine, phenylalanine, tryptophan, tyrosine, serine, theronine, tyrosine, asparagine, cysteine, glutamine, pyrrolysine, selenocysteine, 6-aminohexanoic acid, beta-alanine, and pyrrolysine.[000326] In some aspects, the solid phase lipopeptide synthesis process can begin by attaching a first fatty acid to the N-terminus of the amino acid attached to the N-terminus end of the solid phase peptide. In these embodiments, the result is a first intermediate lipopolipeptide attached to a solid phase, in which the first intermediate lipopolipeptide attached to the solid phase has the structure: [solid phase]-[linker]-[amino acid]m-[lipid]-[cap], where “[linker]” is an amide or an ester and “[cap]” is a small molecule or lipid anhydride. As above, this process can then be repeated as many times as necessary to produce a solid phase lipopeptide according to the formula: [solid phase]-[linker]-[amino acid]n-[lipid]-Z, where Z is OH or NH2 and n is the number of amino acid residues. The solid phase lipopeptide can then be cleaved from the resin to produce the lipopeptide.[000327] In some aspects, the lipopeptide comprising a cationic, cell -penetrating peptide, a linker and a lipid of the lipid nanoparticle (LNP) formulation comprises an amphipathic cationic, cell-penetrating peptide. Cell penetrating peptides can penetrate biological membranes to trigger the movement of various biomolecules across cell membranes into the cytoplasm and to improve their intracellular routing, thereby facilitating interactions with the target. Amphipathic peptides form a specific secondary structure and separate hydrophilic and hydrophobic moieties.[000328] Wyman & al. (1997) Biochemistry 36:3008-17 disclose a low molecular weight cationic amphiphilic peptide, KALA, which mediates nucleic acid delivery and transfection. KALA binds and condenses DNA into small nanoparticles and disrupts endosomes. KALA achieves improved gene expression compared to GALA. However, with 50% ethidiumAtty Docket 5635-0102W01bromide displaced from KALA with charge ratios greater than 1 this indicates that KALA is not highly efficient at compacting DNA. The arginine rich Mu sequence can bind DNA within milliseconds. Other studies have shown that arginine rich sequences are required for nuclear uptake.[000329] Cohen-Avrahami & al. (2011) J. Phys. Chem. B 115:10189-97 and disclose an amphipathic peptide that exhibits improved permeability, 16mer RALA. This enables the enhanced delivery of sodium diclofencac (Na-DFC). This 16 amino acid sequence exhibits improved cell membrane permeability. 16 mer RALA was developed based on GALA with the addition of Arginine (R) residues. This peptide enhances the permeability of cell membranes to deliver a drug. However, the 16 mer RALA has not been used to deliver nucleic acids nor has it been tested in vivo in terms of stability, degradation or immune response.Biologically Active Agents[000330] The LNP compositions of the present disclosure may include one or more therapeutic and / or prophylactic agents. Therapeutic and / or prophylactic agents include biologically active agents. A biologically active agent may be a substance that, once delivered to a cell or organ, brings about a change in the cell, organ, or other bodily tissue or system. Such species may be useful in the treatment of one or more diseases, disorders, or conditions. In some aspects, a biologically active agent is a small molecule drug useful in the treatment of a particular disease, disorder, or condition. Examples of drugs useful in the LNPs include, but are not limited to, antineoplastic agents (e.g., vincristine, doxombicin, mitoxantrone, camptothecin, cisplatin, bleomycin, cyclophosphamide, methotrexate, and streptozotocin), antitumor agents (e.g., actinomycin D, vincristine, vinblastine, cytosine arabinoside, anthracyclines, alkylating agents, platinum compounds, antimetabolites, and nucleoside analogs, such as methotrexate and purine and pyrimidine analogs), anti-infective agents, local anesthetics (e.g., dibucaine and chlorpromazine), beta-adrenergic blockers (e.g., propranolol, timolol, and labetalol), antihypertensive agents (e.g., clonidine and hydralazine), anti-depressants (e.g., imipramine, amitriptyline, and doxepin), anti-convulsants (e.g., phenytoin), antihistamines (e.g., diphenhydramine, chlorpheniramine, and promethazine), antibiotic / antibacterial agents (e.g., gentamycin, ciprofloxacin, and cefoxitin), antifungal agents (e.g., miconazole, terconazole, econazole, isoconazole, butaconazole, clotrimazole, itraconazole, nystatin, naftifine, and amphotericin B). antiparasitic agents, hormones, hormone antagonists, immunomodulators, neurotransmitter antagonists, antiglaucoma agents, vitamins, narcotics, and imaging agents.Atty Docket 5635-0102W01[000331] In some aspects, a biologically active agent is a cytotoxin, a radioactive ion, a chemotherapeutic, a vaccine, a compound that elicits an immune response, and / or another therapeutic and / or prophylactic. A cytotoxin or cytotoxic agent includes any agent that may be detrimental to cells. Examples include, but are not limited to, taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, teniposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracinedione, mitoxantrone, mithramycin, actinomycin D, 1 -dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, maytansinoids, e.g., maytansinol, rachelmycin (CC-1065), and analogs or homologs thereof. Radioactive ions include, but are not limited to iodine (e.g.,125I or131I),89Sr, phosphorous, palladium, cesium, iridium, phosphate, cobalt,90Y,153Sm, and praseodymium. Vaccines include compounds and preparations that can provide immunity against one or more conditions related to infectious diseases such as influenza, measles, human papillomavirus (HPV), rabies, meningitis, whooping cough, tetanus, plague, hepatitis, and tuberculosis and can include mRNAs encoding infectious disease derived antigens and / or epitopes. Vaccines also include compounds and preparations that direct an immune response against cancer cells and can include mRNAs encoding tumor cell derived antigens, epitopes, and / or neoepitopes. Compounds eliciting immune responses may include vaccines, corticosteroids (e.g., dexamethasone), and other species.[000332] In other aspects, a biologically active agent is a polypeptide or protein. Therapeutic proteins useful in the nanoparticles in the disclosure include, but are not limited to, gentamycin, amikacin, insulin, erythropoietin (EPO), granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), Factor VIR, luteinizing hormone-releasing hormone (LHRH) analogs, interferons, heparin, Hepatitis B surface antigen, typhoid vaccine, and cholera vaccine.[000333] In some aspects, a biologically active agent is a polynucleotide or nucleic acid (e.g., ribonucleic acid or deoxyribonucleic acid). The term “polynucleotide,” in its broadest sense, includes any compound and / or substance that is or can be incorporated into a polymer chain of nucleotides. 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, gRNA, shRNA, siRNAs, shRNAs, miRNAs, tRNA, antisense RNAs, ribozymes, catalytic DNA, RNAs that induce triple helix formation, aptamers, vectors, etc. In some aspects, a biologically active agent is an RNA. RNAs useful in the compositions and methodsAtty Docket 5635-0102W01described herein can be selected from the group consisting of, but are not limited to, shortmers, antagomirs, antisense, ribozymes, circular RNA (circRNA), small interfering RNA (siRNA), asymmetrical interfering RNA (aiRNA), microRNA (miRNA), Dicer-substrate RNA (dsRNA), small hairpin RNA (shRNA), transfer RNA (tRNA), messenger RNA (mRNA), and mixtures thereof. In certain aspects, the RNA is an mRNA.[000334] In some aspects, In some aspects, a nucleic acid is a compound and / or substance that is or can be incorporated into a polynucleotide chain via a phosphodiester linkage. In some aspects, nucleic acid is an individual nucleic acid residue (e.g., nucleotides and / or nucleosides). In some aspects, nucleic acid is a polynucleotide chain comprising individual nucleic acid residues. In some aspects, nucleic acid encompasses single and / or double-stranded RNA as well as single and / or double-stranded DNA and / or cDNA. Furthermore, the terms “nucleic acid,” “DNA,” “RNA,” and / or similar terms include nucleic acids from natural sources and nucleic acid analogs, i.e., analogs having other than a phosphodiester backbone. Nucleic acids can be purified from natural sources, produced using recombinant expression systems and optionally purified, chemically synthesized, etc. Where appropriate, e.g., in the case of chemically synthesized molecules, nucleic acids can comprise nucleoside analogs such as analogs having chemically modified bases or sugars, backbone modifications, etc. A nucleic acid sequence of the present disclosure is presented in the 5' to 3' direction unless otherwise indicated. A nucleic acid can comprise natural nucleosides (e.g., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxycytidine); nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and 2-thiocytidine); chemically modified bases; biologically modified bases (e.g., methylated bases); intercalated bases; modified sugars (e.g., 2'-fluororibose, ribose, 2'-deoxyribose, arabinose, and hexose); and / or modified phosphate groups (e.g., phosphorothioates and 5'-N-phosphoramidite linkages).[000335] In certain aspects, a biologically active agent is an mRNA. An mRNA may encode any polypeptide of interest, including any naturally or non-naturally occurring or otherwise modified polypeptide. A polypeptide encoded by an mRNA may be of any size and may haveAtty Docket 5635-0102W01any secondary structure or activity. In some aspects, a polypeptide encoded by an mRNA may have a therapeutic effect when expressed in a cell.[000336] In other aspects, a biologically active agent 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 an LNP 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 aspects, the siRNA may be an immunomodulatory siRNA.Physical Properties[000337] The characteristics of an LNP may depend on the components thereof. For example, an LNP including cholesterol as the sterol component may have different characteristics than an LNP that includes a different sterol. Similarly, the characteristics of an LNP may depend on the absolute or relative amounts of its components. For instance, an LNP including a higher molar fraction of a phospholipid may have different characteristics than an LNP including a lower molar fraction of a phospholipid. Characteristics may also vary depending on the method and conditions of preparation of the LNP.[000338] LNPs may be characterized by a variety of methods. For example, one might examine the morphology and size distribution of an LNP via microscopy (e.g., transmission electron microscopy or scanning electron microscopy). One might use dynamic light scattering or potentiometry (e.g., potentiometric titrations) to measure zeta potentials and / or particle sizes. Instruments such as the Zetasizer Nano ZS (Malvern Instruments Ltd, Malvern, Worcestershire, UK) may also be used to measure multiple characteristics of an LNP, such as particle size, polydispersity index, and zeta potential.[000339] The efficiency of encapsulation of a biologically active agent describes the amount of a biologically active agent that is encapsulated or otherwise associated with an LNP 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 therapeutic and / or prophylactic agent in a solution containing the LNP before and after breaking up the LNP with one or more organic solvents or detergents. Fluorescence may be used to measure the amount of free therapeutic and / or prophylactic agent (e.g., RNA) in a solution. For the LNPs described herein, the encapsulation efficiency of a biologically active agent may be at least 50%, for example at least 55%, at least 60%, at leastAtty Docket 5635-0102WG165%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%.Pharmaceutical Compositions[000340] LNPs may be formulated in whole or in part as pharmaceutical compositions. Pharmaceutical compositions may include one or more LNPs. For example, a pharmaceutical composition may include one or more LNPs including one or more different biologically active agents. Pharmaceutical compositions may further include one or more pharmaceutically acceptable excipients or accessory ingredients such as those described herein. General guidelines for the formulation and manufacture of pharmaceutical compositions and agents are available, for example, in Remington’s The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro; Lippincott, Williams & Wilkins, Baltimore, Md., 2006. Conventional excipients and accessory ingredients may be used in any pharmaceutical composition, except insofar as any conventional excipient or accessory ingredient may be incompatible with one or more components of an LNP. An excipient or accessory ingredient may be incompatible with a component of an LNP if its combination with the component may result in any undesirable biological effect or otherwise deleterious effect.[000341] In some aspects, one or more excipients or accessory ingredients may make up greater than 50% of the total mass or volume of a pharmaceutical composition including an LNP. For example, the one or more excipients or accessory ingredients may make up 50%, 60%, 70%, 80%, 90%, or more of a pharmaceutical convention. In some aspects, a pharmaceutically acceptable excipient is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% pure. In some aspects, an excipient is approved for use in humans and for veterinary use. In some aspects, an excipient is approved by United States Food & Drug Administration. In some aspects, an excipient is pharmaceutical grade. In some aspects, an excipient meets the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and / or the International Pharmacopoeia.[000342] Relative amounts of the one or more LNPs, the one or more pharmaceutically acceptable excipients, and / or any additional ingredients in a pharmaceutical composition in accordance with the present disclosure will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, a pharmaceutical composition may compriseAtty Docket 5635-0102W01between 0.1% and 100% (wt / wt) of one or more LNPs. For example, a pharmaceutical composition as disclosed herein may comprise 0.2%(wt / wt), 0.3%(wt / wt), 0.4%(wt / wt), 0.5%(wt / wt), 0.6%(wt / wt), 0.7%(wt / wt), 0.8% (wt / wt), 0.9%(wt / wt), 1.0%(wt / wt):1.5% (wt / wt), 2.0%(wt / wt), 2.5%(wt / wt), 3.0%(wt / wt), 3.5%(wt / wt), 4.0%(wt / wt) 4.5% (wt / wt), 5.0%(wt / wt), 5.5%(wt / wt), 6.0%(wt / wt), 6.5%(wt / wt), 7.0%(wt / wt) 7.5%(wt / wt), 8.0%(wt / wt), 8.5%(wt / wt), 9.0%(wt / wt), 9.5%(wt / wt), 10%(wt / wt), 12%(wt / wt), 15 %(wt / wt), 17%(wt / wt), 20%(wt / wt), 25%(wt / wt), 30%(wt / wt), 35%(wt / wt), 40%(wt / wt), 45%(wt / wt), 50%(wt / wt), 55%(wt / wt), 60%(wt / wt), 65%(wt / wt), 70%(wt / wt), 75%(wt / wt), 80%(wt / wt), 85%(wt / wt), 90%(wt / wt), 91%(wt / wt), 92%(wt / wt), 93%(wt / wt), 94%(wt / wt), 95%(wt / wt), 96%(wt / wt), 97%(wt / wt), 98%(wt / wt), or 99%(wt / wt) of one or more LNPs.[000343] In certain aspects, the LNPs and / or pharmaceutical compositions of the disclosure are refrigerated or frozen for storage and / or shipment (e.g., being stored at a temperature of 4°C or lower), such as a temperature between about -150°C and about 0°C or between about -80°C and about -20°C (e.g., about -5°C, -10°C, -15°C, -20°C, -25°C, -30°C, -40°C, -50°C, -60°C, -70°C, -80°C, -90°C, -130°C or -150°C). “Stability,” “stabilized,” and “stable” in the context of the present disclosure refers to the resistance of LNPs and / or pharmaceutical compositions disclosed herein to chemical or physical changes (e.g., degradation, particle size change, aggregation, change in encapsulation, etc.) under given manufacturing, preparation, transportation, storage and / or in-use conditions, e.g., when stress is applied such as shear force, freeze / thaw, etc.[000344] LNPs of the disclosure and / or pharmaceutical compositions including one or more LNPs may be administered to any patient or subject, including those patients or subjects that may benefit from a therapeutic effect provided by the delivery of a biologically active agent to one or more particular cells, tissues, organs, or systems or groups thereof. Although the descriptions provided herein of LNPs and pharmaceutical compositions including LNPs are principally directed to compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to any other animal. Modification of compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with merely ordinary experimentation. Non-human subjects to which the compositions may be administered include — but are not limited to — primates andAtty Docket 5635-0102W01other mammals, including commercially relevant mammals (e.g., cows, pigs, horses, sheep, bears, cats, dogs, mice, and / or rats).[000345] A pharmaceutical composition including one or more LNPs may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include bringing the active ingredient into association with an excipient and / or one or more other accessory ingredients. If desirable or necessary, the composition may then be divided, shaped, and / or packaged into a desired single- or multi-dose unit.[000346] 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’’ or “dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient e.g., LNP). 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.[000347] Pharmaceutical compositions may be prepared in a variety of forms suitable for a variety of routes and methods of administration. For example, pharmaceutical compositions of the disclosure may be administered orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularlly, intravitreally, liposomally, locally, mucosally, parenterally, rectally, subconjunctival, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in cremes, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via localized perfusion. Pharmaceutical compositions of the disclosure may be prepared in liquid dosage forms (e.g., emulsions, microemulsions, nanoemulsions, solutions, suspensions, syrups, & elixirs), injectable forms, solid dosage forms (e.g., capsules, tablets, pills, powders, & granules), dosage forms for topical and / or transdermal administration (e.g., ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, & patches), suspensions, powders, and other forms.[000348] Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, nanoemulsions, solutions, suspensions, syrups, and / or elixirs. In addition to active ingredients, liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents,Atty Docket 5635-0102W01solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, & sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, oral compositions can include additional therapeutic and / or prophylactics, additional agents such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and / or perfuming agents. In certain aspects for parenteral administration, compositions are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and / or combinations thereof.[000349] 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.[000350] Injectable formulations can be sterilized, for example, by hitration through a bacterial -retaining biter, 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.[000351] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing compositions with suitable non-irritating excipients such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.[000352] Solid dosage forms for oral administration include capsules, tablets, pills, dims, powders, & granules. In such solid dosage forms, an active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient such as sodium citrate or dicalcium phosphate and / or Ollers or extenders (e.g. starches, lactose, sucrose, glucose, mannitol, & silicic acid), binders (e.g., carbox ymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, &Atty Docket 5635-0102W01acacia), humectants (e.g., glycerol), disintegrating agents (e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, & sodium carbonate), solution retarding agents (e.g., paraffin), absorption accelerators (e.g., quaternary ammonium compounds), wetting agents (e.g., cetyl alcohol & glycerol monostearate), absorbents (e.g., kaolin & bentonite clay, silicates), and lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate), and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may comprise buffering agents.[000353] Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills, & granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions include polymeric substances and waxes. Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.[000354] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include, but are not limited to, short needle devices, jet injection devices, ballistic powder / particle delivery devices, & conventional syringes.[000355] Pharmaceutical compositions formulated for pulmonary delivery may provide an active ingredient in the form of droplets of a solution and / or suspension. Such formulations may be prepared, packaged, and / or sold as aqueous and / or dilute alcoholic solutions and / or suspensions, optionally sterile, comprising active ingredient, and may conveniently be administered using any nebulization and / or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and / or a preservative such as methylhydroxybenzoate. Droplets provided by this route of administration may have an average diameter in the range from about 1 nm to about 200 nm.[000356] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition. Another formulation suitable forAtty Docket 5635-0102W01intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 pm to 500 pm.[000357] 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% (wt / wt) 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 ophthalmically-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 present disclosure.Methods of Delivering Biologically Active Agents to Cells and Organs[000358] The present disclosure provides methods of delivering a biologically active agent to a cell or organ. Delivery of a therapeutic and / or prophylactic to a cell involves administering the composition of the disclosure including the therapeutic and / or prophylactic to a subject, where administration of the composition involves contacting the cell with the composition.[000359] Contacting a nanoparticle composition and a mammalian cell disposed within a mammal may be performed by varied routes of administration (e.g., intravenous, intramuscular, intradermal, and subcutaneous) and may involve varied amounts of nanoparticle compositions. Moreover, more than one mammalian cell may be contacted by a nanoparticle composition.[000360] In one aspect, the composition of the present disclosure may be administered using intravenous, intramuscular, intradermal, subcutaneous, or other methods of delivering a composition to a subject. In one aspect, the composition of the disclosure may be selected to target delivery to a specific region or system of a body.Methods of Treating Diseases[000361] Compositions of the disclosure may be useful for treating a disease, disorder, or condition. In particular, such compositions may be useful in treating a disease, disorder, or condition characterized by missing or aberrant polypeptide activity. For example, the LNPs and formulations described herein may be useful for treating vascular diseases by utilizing targeted delivery of siRNA and mRNA therapeutics to vascular injury and atheroscleroticAtty Docket 5635-0102W01plaques. Treatments using such LNPs and formulations may improve patient outcomes in atherosclerosis and endovascular procedures.[000362] A disease, disorder, or condition characterized by missing or aberrant polypeptide activity can be treated by administering to the patient an LNP as disclosed herein. An LNP comprising 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. A therapeutic and / or prophylactic agent included in a nanoparticle composition may also be capable of altering the rate of transcription of a given species, thereby affecting gene expression.[000363] Typical subjects include animals (e.g., mice, rats, rabbits, non-human primates, and humans) and / or plants. Patients are subjects who may be seeking or be in need of treatment, require treatment, are receiving treatment, will receive treatment, or a individual who is under care by a trained professional for a particular disease or condition.[000364] Diseases, disorders, and / or conditions characterized by dysfunctional or aberrant protein or polypeptide activity for which a composition of the disclosure 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, lysosomal storage disorders, & 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. The present disclosure provides methods for treating such diseases, disorders, and / or conditions in a subject by administering an LNP. In certain embodiments, the LNP includes a nucleic acid (e.g., an mRNA) encoding a polypeptide that antagonizes or otherwise overcomes an aberrant protein activity present in the cell of the subject.[000365] An LNP including one or more therapeutic and / or prophylactic agents may be administered by any route. In some embodiments, compositions, including prophylactic, diagnostic, or imaging compositions including one or more nanoparticle compositions described herein, are administered by one or more of a variety of routes, including oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraparenchymal, subcutaneous, intraventricular, trans- or intra-dermal, interdermal, rectal, intravaginal,Atty Docket 5635-0102W01intraperitoneal, intraocular, subretinal, intravitreal, topical (e.g. by powders, ointments, creams, gels, lotions, and / or drops), mucosal, nasal, buccal, enteral, vitreal, intratumoral, sublingual, intranasal; by intratracheal instillation, bronchial instillation, and / or inhalation; as an oral spray and / or powder, nasal spray, and / or aerosol, and / or through a portal vein catheter. In some embodiments, a composition may be administered intravenously, intramuscularly, intradermally, intra-arterially, intratumorally, subcutaneously, intraocularly, subretinally, intravitreally, intraparenchymally or by any other parenteral route of administration or by inhalation. However, the present disclosure encompasses the delivery or administration of compositions described herein by any appropriate route taking into consideration likely advances in the sciences of drug delivery. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the LNP composition including one or more therapeutic and / or prophylactic agents (e.g., its stability in various bodily environments such as the bloodstream and gastrointestinal tract), the condition of the patient (e.g., whether the patient is able to tolerate particular routes of administration), etc.[000366] It will further be appreciated that therapeutically, prophylactically, diagnostically, or imaging active agents utilized in combination may be administered together in a single composition or administered separately in different compositions. In general, it is expected that agents utilized in combination will be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination may be lower than those utilized individually.[000367] 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. The therapies employed may achieve a desired effect for the same disorder (for example, a composition useful for treating cancer may be administered concurrently with a chemotherapeutic agent), or they may achieve different effects (e.g., control of any adverse effects, such as infusion related reactions).[000368] A LNP composition may be used in combination with an agent to increase the effectiveness and / or therapeutic window of the composition. Such an agent may be, for example, an anti-inflammatory compound, a steroid (e.g., a corticosteroid), a statin, an estradiol, a BTK inhibitor, an SIP 1 agonist, a glucocorticoid receptor modulator (GRM), or an anti-histamine.Atty Docket 5635-0102WG1[000369] Compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry’: Reactions, Mechanisms, & Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure.Table 2. Sequences of the DisclosureEXAMPLESExample 1: Synthesis of Lipopeptides[000370] Lipopeptides of the present disclosure are synthesized using a Fmoc-peptide method. For example, a suitable method is described in Collins & al. (2014) “High-efficiency solid phase peptide synthesis (HE-SPPS)” Organic letters 16(3):940-43. First, the peptide portion of a lipopeptide of the present disclosure is synthesized. During the peptide portion of synthesis, free carboxylic acid containing molecules having no free amines are added to a resin (e.g., a polystyrene resin, such as Fmoc-Gly Wang PS, Fmoc-Tyr(tBu)-Wang PS, MBHA-PS, or PAL-PEG-PS) pre-bound to a single or chain of residues containing a deprotected amine inAtty Docket 5635-0102W01the presence of activating chemicals (e.g., carbodiimide additives such as HOBt, HO At, and Oxyma) for a peptide bond to form. The deprotection step can be accomplished in one minute at 90°C and the coupling step in two minutes at 90°C by using microwave irradiation to supply the heat, and with an internal fiber optic probe to monitor and control the rate of heating. The resin is washed, and the process repeated until the desired peptide portion is achieved. Only 3 washes of 1, 2, & 3 mL N-methyl-2-pyrrolidone or 2, 2, & 3 mL dimethylformamide (DMF) will suffice for standard polystyrene resins at 50°C, although four washes of 4 mL PALPEG-PS resin may be necessary after the deprotection step because of its higher mass from lower substitution. Post-coupling wash steps may be omitted. The lipid capping (N-tenuinal peptide modification) occurs by the same process as the amino acid additions. The last step of adding the lipid may be a single or repetitive addition to ensure all of the free amines are reacted to that fatty acid (or anhydride).[000371] The lipid capping process can be achieved using a method known in the art, for example, by capping with small molecule or lipid anhydride, which as acetic anhydride or stearic anhydride which is more applicable to this discussion. Alternatively, lipid capping can be achieved by treating a fatty acid, or PL-containing a carboxyl group for reaction with the N-terminus.[000372] The peptide portion of the lipopeptide was built in a series of additions from the C-terminus to N-terminus, the first amino acid that is reacted with a solid phase resin is the C-temiinal amino acid, subsequently, more amino acids are added sequentially according to the desired lipopeptide design. For example, one embodiment of a single amino acid addition is NH2 -Arg-Resin. The process was repeated, for example by adding an additional amino acid to achieve NH2-Arg-Arg-Resin, until the last step when an anhydride or acid is reacted to cap the N-terminus side. Where the N-terminus of the peptide is an acetyl group or a PL group (e.g., Acetyl-Arg8-resin, or PL-succinyl-Arg8-resin), the lipopeptide intermediate is chemically removed (or cleaved) from the resin, for example, to provide PL-succinyl-Arg8 peptide.[000373] The method described above was followed for lipid addition to internal residues, for example using the R-group amine of lysine, by selective deprotection then addition of acetyl, stearyl, biotin, PL, or a combination thereof.[000374] In addition, it is to be understood that any particular aspect of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims.Atty Docket 5635-0102W01Since such aspects are deemed to be part of the whole of the present disclosure, any part of the whole disclosure may be excluded even if the exclusion is not set forth explicitly herein.[000375] It is to be understood that while the present disclosure has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the present disclosure, which is defined by the scope of the appended claims. Other aspects, advantages, and alterations are within the scope of the following claims.

Claims

Atty Docket 5635-0102W01CLAIMS1. A lipid nanopaiticle (LNP) formulation comprising:(i) a phospholipid;(ii) a sterol;(iii) a polyethylene glycol-conjugated lipid (PEG-lipid); and(iv) a lipopeptide comprising a cationic, cell-penetrating peptide, a linker and a lipid.

2. The LNP formulation of claim 1, wherein the LNP comprises about 10-50 mol-% phospholipid, about 20-50 mol-% sterol, about 1-10 mol-% PEG-lipid, and about 1- 20 mol-% lipopeptide.

3. The LNP formulation of claim 1 or claim 2, wherein the phospholipid is 1 ,2-dioleoyl- sn-glycero-3-phosphocholine (DOPC), l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), l,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dilinoleoyl-sn- glycero-3-phosphocholine (DLPC), 1 ,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), l,2-dioleoyl-sn-glycero-3 -phosphocholine (DOPC), 1,2-dipalmitoyl-sn- glycero-3-phosphocholine (DPPC), 1 ,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), l-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O- octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), l-oleoyl-2- cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1 -hexadecyl- sn-glycero-3 -phosphocholine (C16 Lyso PC), l,2-dilinolenoyl-sn-glycero-3- phosphocholine, l,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2- didocosahexaenoyl-sn-glycero-3-phosphocholine, l,2-diphytanoyl-sn-glycero-3- phosphoethanolamine (ME 16.0 PE), l,2-distearoyl-sn-glycero-3- phosphoethanolamine, 1 ,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1 ,2- dilinolenoyl-sn-glycero-3-phosphoethanolamine, l,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), and sphingomyelin, or any combination thereof.

4. The LNP formulation of any one of the previous claims, wherein the sterol is cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, tomatine, ursolic acid, alpha-tocopherol, and mixtures thereof.Atty Docket 5635-0102WG15. The LNP formulation of any one of the previous claims, wherein the lipopeptide comprises a peptide, a linker and a lipid according to the formula (peptide)-(linker)- (lipid) in the N-terminal to C-terminal direction.

6. The LNP formulation of any one of the previous claims, wherein the peptide is an oligoarginine, a homoarginine, or a combination thereof.

7. The LNP formulation of claim 6, wherein the oligoarginine consists of 2-50 arginine residues.

8. The LNP formulation of claim 7, wherein the oligoarginine consists of 8-12 arginine residues.

9. The LNP formulation of claim 8, wherein the oligoarginine consists of 8 arginine residues (R8).

10. The LNP formulation of any one of claims 6-9, wherein the oligoarginine comprises SEQ ID NO: 2.

11. The LNP formulation of any one of the previous claims, wherein the linker is an amide or an ester.

12. The LNP formulation of claim 11, wherein the ester is thiol ether.

13. The LNP formulation of claim 11, wherein the amide is CONH2, N-succinyl, N- glutaryl, or N-dodecanoyl.

14. The LNP formulation of any one of the previous claims, wherein the linker is a cleavable linker.

15. The LNP formulation of any one of the previous claims, wherein the PEG-lipid is a PEG-modified phosphatidylethanolamines, PEG-modified phosphatidic acids, PEG- modified ceramides, PEG-modified dialkylamines, PEG-modified diacylglycerols, PEG-modified dialkylglycerols, or a combination thereof.

16. The LNP formulation of any one of the previous claims, wherein the lipid is one or more ionizable lipids.

17. The LNP formulation of any one of the previous claims, wherein the lipid is one or more fatty acids.

18. The LNP formulation of claim 17, wherein the one or more fatty acids is a heptadecan- 9-yl, a 2,2-dimethylpropanoyl, a 1 ,2-dioleoyl, an ionisable aminolipid, a Dlin, aAtty Docket 5635-0102WG1didodecyl, a stearic fatty acid, a caprylic acid, a capric acid, a lauric acid, a mystristic acid, a palmitic acid, a steraric acid, a palmitoletic acid, an oleic acid, a linoleic acid, a linolenic acid, an a-eleostearic acid, a ricinoletic acid, a vemolic acid, a eicosatetraenoic acid, eicosapentaenoic acid, a di-DHA-PE, a docosahexaenoic acid (DHA), a alpha- eleostreayl fatty acid, a 1 ,2-dipalmitoleoyl-PE, a 1,2-dilinoleoyl PE, a 1 ,2-dilinoleoyl PG, a di-arachidonoyl PE, a di-arachidonoyl PG, a 1 ,2-dipalmitoyl-sn-Glycero, a 18:1 1,2-dioleoyl-sn-glycero or a combination thereof.

19. The LNP formulation of claim 5, wherein the lipopeptide comprises a peptide, a linker and a lipid according to the formula (R8)-(amide)-(dipalmitoleoyl-PE), (R8)-(amide)- (dipalmitoyl-PE), (R8)-(amide)-(palmitoleic acid), (R8)-(ester)-(dilinoleoyl-PG), (R8)- (ester)-(dipalmitoleoyl-PE), (R9)-(amide)-(dipahnitoleoyl-PE), (R9)-(amide)- (palmitoleic acid), (R9)-(ester)-(dilinoleoyl-PG), (R9)-(ester)-(dipalmitoleoyl-PE), (R10)-(amide)-(oleic acid), (R10)-(amide)-(palmitoleic acid), (RlO)-(ester)- (palmitoleic acid), (Rll)-(amide)-(palmitoleic acid), or (R12)-(amide)-(palmitoleic acid).

20. The LNP formulation of any one of the previous claims, wherein the lipopeptide is LL- 1-24001, LL-1-24002, LL-1-24003, LL-1-24004, LL- 1-24005, LL- 1-24006, LL-1- 24007, LL- 1-24008, LL- 1-24009, LL- 1-24010, LL-1 -24011, LL- 1-24012, LL-1- 24013, LL- 1-24014, LL- 1-24015, LL- 1-24016, LL-1-24017, LL- 1-24018. LL-1- 24019, LL- 1-24020, LL- 1-24021, LL- 1-24022, LL- 1-24023, LL- 1-24024, LL-1- 24025, LL- 1-24026, LL-1-24027, LL- 1-24028, LL- 1-24029, LL- 1-24030, LL-1- 24031, LL-1-24032, LL-1-24033, LL- 1-24034, LL- 1-24035, LL- 1-24036, LL-1- 24037, LL- 1-24038, LL- 1-24039, LL- 1-24040. LL- 1-24041, LL- 1-24042, LL-1- 24043, LL- 1-24044, LL- 1-24045, LL- 1-24046, LL-1 -24047, LL- 1-24048, LL-1- 24049, LL-1 -24050, LL-1 -24051, LL-1 -24052, LL-1 -24053, LL-1 -24054, LL-1- 24055, LL-1 -24056, LL-1 -24057, LL-1 -24058, LL-1 -24059, LL-1 -24060, LL-1- 24061, LL-1 -24062. LL-1 -24063, LL-1 -24064, LL-1 -24065, LL-1 -24066, LL-1- 24067, LL-1 -24068, LL-1 -24069, LL-1 -24070, LL-1 -24071, LL-1 -24072, LL-1- 24073, LL-1 -24074, LL-1 -24075, LL-1 -24076, LL-1 -24077, LL-1 -24078, LL-1- 24079, LL-1 -24080, LL-1 -24081, LL-1 -24082, LL-1 -24083, LL-1 -24084, LL-1- 24085, LL-1-24086, LL-1 -24087, LL-1 -24088, LL-1 -24089, LL-1 -24090, LL-1- 24091, LL-1 -24092, LL-1 -24093, LL-1 -24094, LL-1 -24095, LL-1 -24096, LL-1- 24097, LL-1 -24098, LL-1 -24099, LL-1 -24100, LL-1 -24101, LL-1 -24102, LL-1-Atty Docket 5635-0102W0124103, LL- 1-24104, LL- 1-24105, LL- 1-24106, LL- 1-24107, LL- 1-24108, LL-1- 24109, LL- 1-24110, LL-1-24111, LL- 1-24112, LL-1-24113, LL- 1-24114, LL-1- 24115, LL- 1-24116, LL-1-24117, LL- 1-24118, LL- 1-24119, LL- 1-24120, LL-1- 24121, LL- 1-24122, LL- 1-24123, LL- 1-24124, LL-1 -24125, LL- 1-24126, LL-1- 24127, LL- 1-24128, LL- 1-24129, LL- 1-24130, LL- 1-24131, LL- 1-24132, LL-1- 24133, LL- 1-24134. LL- 1-24135, LL- 1-24136, LL- 1-24137, LL- 1-24138, LL-1- 24139, LL- 1-24140, LL-1-24141, LL- 1-24142, LL- 1-24143, LL- 1-24144. LL-1- 24145, LL- 1-24146, LL-1-24147, LL- 1-24148, LL-1-24149, LL-1 -24150, LL-1- 24151, LL-1-24152, LL-1-24153, LL-1 -24154, LL-1 -24155, LL-1-24156, LL-1- 24157, LL-1-24158, LL-1-24159, LL-1 -24160, LL-1-24161, LL-1 -24162, LL-1- 24163, LL-1 -24164, LL-1 -24165, LL-1 -24166. LL-1 -24167, LL-1 -24168, LL-1- 24169, LL-1 -24170, LL-1-24171, LL-1 -24172, LL-1-24173, LL-1 -24174, LL-1- 24175, LL-1-24176, LL-1-24177, LL-1 -24178, LL-1-24179, LL-1 -24180, LL-1- 24181, LL-1 -24182, LL-1-24183, LL-1 -24184, LL-1 -24185, LL-1-24186, LL-1- 24187, LL-1-24188. LL-1-24189, LL-1 -24190, LL-1-24191, LL-1 -24192, LL-1- 24193, LL-1 -24194, LL-1 -24195, LL-1 -24196, LL-1 -24197, LL-1 -24198. LL-1- 24199, LL-1 -24200, LL-1 -24201, LL-1 -24202, LL-1 -24203, LL-1 -24204, LL-1- 24205, LL-1 -24206, LL-1 -24207, LL-1 -24208, LL-1 -24209, LL-1 -24210, LL-1- 24211, LL-1 -24212, LL-1-24213, LL-1 -24214, LL-1 -24215, LL-1 -24216, LL-1- 24217, LL-1 -24218, LL-1 -24219, LL-1 -24220, LL-1 -24221, LL-1 -24222, LL-1- 24223, LL-1 -24224, LL-1 -24225, LL-1 -24226, LL-1 -24227, LL-1 -24228, LL-1- 24229, LL-1 -24230, LL-1 -24231, LL-1 -24232, LL-1 -24233, LL-1 -24234, LL-1- 24235, LL-1-24236, LL-1 -24237, LL-1 -24238, LL-1 -24239, LL-1 -24240, LL-1- 24241, LL-1 -24242, LL-1 -24243, LL-1 -24244, LL-1 -24245, LL-1 -24246, LL-1- 24247, LL-1 -24248, LL-1 -24249, LL-1 -24250, or a combination thereof.

21. The LNP formulation of any one of the previous claims, wherein the LNP formulation encapsulates a therapeutic, diagnostic, and / or prophylactic agent.

22. The LNP formulation of claim 21, wherein the therapeutic, diagnostic, and / or prophylactic agent is a nucleic acid.

23. The LNP formulation of claim 22, wherein the nucleic acid is an RNA or DNA molecule.

24. The LNP formulation of claim 23, wherein the nucleic acid is an RNA molecule.Atty Docket 5635-0102W0125. The LNP formulation of claim 23, wherein the nucleic acid is a DNA molecule.

26. The LNP formulation of claim 25, wherein the DNA is a double stranded DNA (dsDNA).

27. The LNP formulation of claim 25, wherein DNA is a single stranded DNA (ssDNA).

28. The LNP formulation of any one of claims 22-27, wherein the nucleic acid is a linear nucleic acid molecule.

29. The LNP formulation of any one of claims 22-27, wherein the nucleic acid is a circular nucleic acid molecule.

30. The LNP formulation of claim 24, wherein the RNA is a circRNA, an siRNA, an miRNA, an shRNA, a tRNA, or an mRNA.

31. The LNP formulation of claim 30, wherein the RNA is an mRNA.

32. A method for delivering an mRNA into a cell, the method comprising contacting the cell with the LNP formulation of claim 31.

33. The method of claim 32, wherein, prior to contacting, the cell exhibits an aberrant expression or activity of a protein encoded by the mRNA.

34. The method of claim 33, wherein the aberrant expression or activity of the protein comprises an expression of a non-functional variant of said protein.

35. The method of claim 34, wherein the aberrant expression or activity of the protein is associated with a genetic disease or disorder.

36. The method of claim 35, wherein the mRNA is expressed in the cell, upon the contacting, to produce a functional variant of the protein.

37. The method of claim 36, wherein expression of the mRNA in the cell increases an amount of a functional variant of the protein as compared to an amount of the functional variant of the protein generated in absence of the contacting.

38. The method of any one of claims 32-37, wherein the contacting is in vivo.

39. The method of any one of claims 32-38, wherein the cell is in a tissue or organ of a subject.

40. The method of claim 39, wherein the tissue or organ is a functionally compromised tissue or organ.Atty Docket 5635-0102W0141. The method of claim 40, wherein the contacting comprises administering to the subject the LNP formulation.

42. The method of any one of claims 32-41, further comprising repeating the contacting.

43. A pharmaceutical composition comprising the LNP formulation of any one of claims 21-31, and a pharmaceutically acceptable carrier.

44. A method of delivering a therapeutic, diagnostic, and / or prophylactic agent to a cell, the method comprising administering to a subject the LNP formulation of any one of claims 21-31, wherein the administering comprises contacting the cell with the LNP, whereby the therapeutic, diagnostic, and / or prophylactic agent is delivered to the cell.

45. A method of delivering a therapeutic, diagnostic, and / or prophylactic agent to a cell of a subject, the method comprising administering the pharmaceutical composition of claim 43 to the subject.

46. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the LNP formulation of any one of claims 21-31.

47. The method of any one of claims 44—46, wherein the LNP formulation or the pharmaceutical composition is formulated for administration orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularlly, intravitreally, liposomally, locally, mucosally, parenterally, rectally, subconjunctival, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in cremes, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via localized perfusion.

48. A kit for making a gene therapy system, comprising the the LNP formulation of any one of claims 1-31 and a buffer, a pharmaceutically acceptable carrier, and / or a protocol to make said gene therapy system or pharmaceutical composition.

49. A lipopeptide, wherein the lipopeptide is selected from the group consisting of LL-1- 24001, LL- 1-24002, LL- 1-24003, LL- 1-24004, LL- 1-24005, LL- 1-24006, LL-1- 24007, LL- 1-24008, LL- 1-24009, LL- 1-24010, LL-1-24011, LL- 1-24012, LL-1-Atty Docket 5635-0102W0124013, LL-1-24014, LL-1 -24015, LL-1 -24016, LL-1 -24017, LL-1 -24018, LL-1- 24019, LL- 1-24020, LL-1 -24021, LL-1 -24022, LL-1 -24023, LL- 1-24024, LL-1- 24025, LL- 1-24026, LL-1-24027, LL-1 -24028, LL-1 -24029, LL-1-24030, LL-1- 24031, LL- 1-24032, LL-1 -24033, LL-1 -24034, LL-1 -24035, LL- 1-24036, LL-1- 24037, LL-1 -24038, LL-1 -24039, LL-1 -24040, LL-1 -24041, LL- 1-24042, LL-1- 24043, LL-1-24044, LL-1 -24045, LL-1 -24046, LL-1 -24047, LL- 1-24048, LL-1- 24049, LL-1 -24050, LL-1 -24051, LL-1 -24052, LL-1 -24053, LL- 1-24054, LL-1- 24055, LL-1 -24056, LL-1 -24057, LL-1 -24058, LL-1 -24059, LL- 1-24060, LL-1- 24061, LL-1 -24062, LL-1 -24063, LL-1 -24064, LL-1 -24065, LL- 1-24066, LL-1- 24067, LL-1-24068, LL-1 -24069, LL-1 -24070, LL-1 -24071, LL-1-24072, LL-1- 24073, LL-1 -24074, LL-1 -24075, LL-1 -24076, LL-1 -24077, LL- 1-24078, LL-1- 24079, LL-1 -24080, LL-1 -24081, LL-1 -24082, LL-1 -24083, LL- 1-24084, LL-1- 24085, LL-1 -24086, LL-1-24087, LL-1 -24088, LL-1 -24089, LL- 1-24090, LL-1- 24091, LL-1 -24092, LL-1-24093, LL-1 -24094, LL-1 -24095, LL- 1-24096, LL-1- 24097, LL-1-24098. LL-1 -24099, LL-1 -24100, LL-1-24101, LL- 1-24102, LL-1- 24103, LL-1-24104, LL-1 -24105, LL-1 -24106, LL-1-24107, LL- 1-24108, LL-1- 24109, LL-1 -24110, LL-1-24111, LL-1 -24112, LL-1-24113, LL-1-24114, LL-1- 24115, LL-1-24116, LL-1-24117, LL-1 -24118, LL-1-24119, LL- 1-24120, LL-1- 24121, LL-1-24122, LL-1-24123, LL-1 -24124, LL-1 -24125, LL- 1-24126, LL-1- 24127, LL-1-24128, LL-1 -24129, LL-1 -24130. LL-1-24131, LL-1-24132, LL-1- 24133, LL-1 -24134, LL-1-24135, LL-1 -24136, LL-1-24137, LL-1-24138, LL-1- 24139, LL-1-24140, LL-1-24141, LL-1 -24142, LL-1-24143, LL- 1-24144, LL-1- 24145, LL-1-24146, LL-1 -24147, LL-1 -24148, LL-1-24149, LL- 1-24150, LL-1- 24151, LL-1-24152, LL-1-24153, LL-1 -24154, LL-1-24155, LL- 1-24156, LL-1- 24157, LL-1-24158, LL-1-24159, LL-1 -24160, LL-1-24161, LL- 1-24162, LL-1- 24163, LL-1-24164, LL-1-24165, LL-1 -24166, LL-1-24167, LL- 1-24168, LL-1- 24169, LL-1-24170, LL-1-24171, LL-1 -24172, LL-1-24173, LL- 1-24174, LL-1- 24175, LL-1-24176, LL-1 -24177, LL-1 -24178, LL-1-24179, LL- 1-24180, LL-1- 24181, LL-1-24182, LL-1 -24183, LL-1 -24184, LL-1 -24185, LL- 1-24186, LL-1- 24187, LL-1-24188, LL-1-24189, LL-1 -24190, LL-1-24191, LL- 1-24192, LL-1- 24193, LL-1-24194, LL-1-24195, LL-1 -24196, LL-1-24197, LL- 1-24198, LL-1- 24199, LL-1 -24200, LL-1 -24201, LL-1 -24202, LL-1 -24203, LL- 1-24204, LL-1- 24205, LL-1 -24206, LL-1 -24207, LL-1 -24208, LL-1 -24209, LL- 1-24210, LL-1-Atty Docket 5635-0102WG124211, LL-1-24212, LL-1-24213, LL-1-24214, LL-1-24215, LL-1-24216, LL-1- 24217, LL- 1-24218, LL- 1-24219, LL- 1-24220, LL- 1-24221, LL- 1-24222, LL-1- 24223, LL-1-24224, LL-1-24225, LL-1-24226, LL-1-24227, LL-1-24228, LL-1- 24229, LL-1-24230, LL-1-24231, LL-1-24232, LL-1-24233, LL-1-24234, LL-1- 24235, LL-1-24236, LL-1-24237, LL-1-24238, LL-1-24239, LL-1-24240, LL-1- 24241, LL-1-24242. LL-1-24243, LL-1-24244, LL-1-24245, LL-1-24246, LL-1- 24247, LL- 1-24248, LL- 1-24249, and LL- 1-24250.

50. A lipopeptide, wherein the lipopeptide comprises a peptide, a linker and a lipid according to the formula (R8)-(amide)-(dipalmitoleoyl-PE), (R8)-(amide)- (dipalmitoyl-PE), (R8)-(amide)-(palmitoleic acid), (R8)-(ester)-(dilinoleoyl-PG), (R8)- (ester)-(dipalmitoleoyl-PE), (R9)-(amide)-(dipalmitoleoyl-PE), (R9)-(amide)- (palmitoleic acid), (R9)-(ester)-(dilinoleoyl-PG), (R9)-(ester)-(dipalmitoleoyl-PE), (R10)-(amide)-(oleic acid), (R10)-(amide)-(palmitoleic acid), (RlO)-(ester)- (palmitoleic acid), (Rll)-(amide)-(palmitoleic acid), or (R12)-(amide)-(palmitoleic acid).

51. A method for synthesizing the lipopeptide of claim 49 or 50, comprising first performing solid phase peptide synthesis followed by performing solid phase lipopeptide synthesis and separated from the solid phase.

52. The method of claim 51, wherein the solid phase peptide synthesis comprise:a) attaching a first carboxylic acid containing molecule having no free amines to a solid phase in the presence of activating chemicals, wherein the carboxylic acid containing molecule having no free amines attached to a solid phase iswherein K is a solid phase,linker is an amide or an ester,Fmoc is a fluorenylmethoxycarbonyl protecting group,R is an amino acid side chain,Y is a side chain protecting group, andAtty Docket 5635-0102W01X is O or NH;b) washing the resin;c) attaching a second carboxylic acid containing molecule having no free amines to the N terminus of the first carboxylic acid having no free amines attached to the solid phase in the presence of activating chemicals;d) washing the resin;e) repeating steps a) to d) m times to produce a solid phase peptide, wherein the solid phase peptide iswherein m is independently selected from 1-5053. The method of claim 52, wherein the solid phase is a resin.

54. The method of claim 52, wherein the amino acid side chain is independently selected from the side chains of alanine, isoleucine, leucine, methionine, valine, proline, glycine, aspartic acid, glutamic acid, arginine, histidine, lysine, phenylalanine, tryptophan, tyrosine, serine, theronine, tyosine, asparagine, cysteine, glutamine, pyrrolysine, selenocysteine, and pyrrolysine.

55. The method of claim any one of claims 52-54, wherein the solid phase lipopeptide synthesis comprise:a) attaching a first fatty acid to the N-terminus of the amino acid attached to the N- terminus end of the solid phase peptide in the presence of activating chemicals to produce a first intermediate lipopoli peptide attached to a solid phase, wherein the first intermediate lipopolipeptide attached to a solid phase is[solid phase]-[linker]-[amino acid]m-[lipid]-[cap] wherein linker is an amide or an ester,wherein cap is a small molecule or lipid anhydride,b) washing the resin;c) attaching a second fatty acid to the N terminus of the first intermediate lipopolipeptide attached to the solid phase in the presence of activating chemicals;Atty Docket 5635-0102W01d) washing the resin;e) repeating steps a) to d) n times to produce a solid phase lipopeptide, wherein the solid lipophase peptide is[solid phase]-[linker]-[amino acid]n-[lipid]-Z wherein Z is OH or NH2, andwherein n is independently selected from 1-5056. The method of claim 55, wherein the solid phase lipopeptide is cleaved from the resin to produce the lipopeptide.

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