INCORPORATION-BY-REFERENCE OF SEQUENCE LISTING

The contents of the text file named “MRNA014001WOST25.txt”, which was created on Dec. 2, 2016 and is 1 KB in size, are hereby incorporated by reference in their entireties.

FIELD OF DISCLOSURE

The present disclosure provides novel compounds, compositions comprising such compounds, and methods involving lipid nanoparticle compositions to deliver one or more therapeutic and/or prophylactics to and/or produce polypeptides in mammalian cells or organs. In addition to a novel lipid, lipid nanoparticle compositions of the disclosure may include one or more cationic and/or ionizable amino lipids, phospholipids including polyunsaturated lipids, PEG lipids, structural lipids, and/or therapeutic and/or prophylactics in specific fractions.

BACKGROUND OF THE DISCLOSURE

The effective targeted delivery of biologically active substances such as small molecule drugs, proteins, and nucleic acids represents a continuing medical challenge. In particular, the delivery of nucleic acids to cells is made difficult by the relative instability and low cell permeability of such species. Thus, there exists a need to develop methods and compositions to facilitate the delivery of therapeutic and/or prophylactics such as nucleic acids to cells.

Lipid-containing nanoparticle compositions, liposomes, and lipoplexes have proven effective as transport vehicles into cells and/or intracellular compartments for biologically active substances such as small molecule drugs, proteins, and nucleic acids. Such compositions generally include one or more “cationic” and/or amino (ionizable) lipids, phospholipids including polyunsaturated lipids, structural lipids (e.g., sterols), and/or lipids containing polyethylene glycol (PEG lipids). Cationic and/or ionizable lipids include, for example, amine-containing lipids that can be readily protonated. Though a variety of such lipid-containing nanoparticle compositions have been demonstrated, improvements in safety, efficacy, and specificity are still lacking.

SUMMARY OF THE DISCLOSURE

The present disclosure provides novel compounds and compositions and methods involving the same.

A first aspect of the disclosure relates to compounds of Formula (I):



or a salt or isomer thereof, wherein:

R1is selected from the group consisting of C5-30alkyl, C5-20alkenyl, —R*YR″, —YR″, and —R″M′R′;

R2and R3are independently selected from the group consisting of H, C1-14alkyl, C2-14alkenyl, —R*YR″, —YR″, and —R*OR″, or R2and R3, together with the atom to which they are attached, form a heterocycle or carbocycle;

R4is selected from the group consisting of a C3-6carbocycle, —(CH2)nQ, —(CH2)nCHQR, —CHQR, —CQ(R)2, and unsubstituted C1-6alkyl, where Q is selected from a carbocycle, heterocycle, —OR, —O(CH2)nN(R)2, —C(O)OR, —OC(O)R, —CX3, —CX2H, —CXH2, —CN, —N(R)2, —C(O)N(R)2, —N(R)C(O)R, —N(R)S(O)2R, —N(R)C(O)N(R)2, —N(R)C(S)N(R)2, —N(R)R8, —O(CH2)nOR, —N(R)C(═NR9)N(R)2, —N(R)C(═CHR9)N(R)2, —OC(O)N(R)2, —N(R)C(O)OR, —N(OR)C(O)R, —N(OR)S(O)2R, —N(OR)C(O)OR, —N(OR)C(O)N(R)2, —N(OR)C(S)N(R)2, —N(OR)C(═NR9)N(R)2, —N(OR)C(═CHR9)N(R)2, —C(═NR9)N(R)2, —C(═NR9)R, —C(O)N(R)OR, and —C(R)N(R)2C(O)OR, and each n is independently selected from 1, 2, 3, 4, and 5;

each R5is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

each R6is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

M and M′ are independently selected from —C(O)O—, —OC(O)—, —C(O)N(R′)—, —N(R′)C(O)—, —C(O)—, —C(S)—, —C(S)S—, —SC(S)—, —CH(OH)—, —P(O)(OR′)O—, —S(O)2—, —S—S—, an aryl group, and a heteroaryl group;

R7is selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

R8is selected from the group consisting of C3-6carbocycle and heterocycle;

R9is selected from the group consisting of H, CN, NO2, C1-6alkyl, —OR, —S(O)2R, —S(O)2N(R)2, C2-6alkenyl, C3-6carbocycle and heterocycle;

each R is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

each R′ is independently selected from the group consisting of C1-18alkyl, C2-18alkenyl, —R*YR″, —YR″, and H;

each R″ is independently selected from the group consisting of C3-14alkyl and C3-14alkenyl;

each R* is independently selected from the group consisting of C1-12alkyl and C2-12alkenyl;

each Y is independently a C3-6carbocycle;

each X is independently selected from the group consisting of F, Cl, Br, and I; and

m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13.

In some embodiments, a subset of compounds of Formula (I) includes those in which when R4is —(CH2)nQ, —(CH2)nCHQR, —CHQR, or —CQ(R)2, then (i) Q is not —N(R)2when n is 1, 2, 3, 4 or 5, or (ii) Q is not 5, 6, or 7-membered heterocycloalkyl when n is 1 or 2.

In another embodiments, another subset of compounds of Formula (I) includes those in which

R1is selected from the group consisting of C5-30alkyl, C5-20alkenyl, —R*YR″, —YR″, and —R″M′R′;

R2and R3are independently selected from the group consisting of H, C1-14alkyl, C2-14alkenyl, —R*YR″, —YR″, and —R*OR″, or R2and R3, together with the atom to which they are attached, form a heterocycle or carbocycle;

R4is selected from the group consisting of a C3-6carbocycle, —(CH2)nQ, —(CH2)nCHQR, —CHQR, —CQ(R)2, and unsubstituted C1-6alkyl, where Q is selected from a C3-6carbocycle, a 5- to 14-membered heteroaryl having one or more heteroatoms selected from N, O, and S, —OR, —O(CH2)nN(R)2, —C(O)OR, —OC(O)R, —CX3, —CX2H, —CXH2, —CN, —C(O)N(R)2, —N(R)C(O)R, —N(R)S(O)2R, —N(R)C(O)N(R)2, —N(R)C(S)N(R)2, —CRN(R)2C(O)OR, —N(R)R8, —O(CH2)nOR, —N(R)C(═NR9)N(R)2, —N(R)C(═CHR9)N(R)2, —OC(O)N(R)2, —N(R)C(O)OR, —N(OR)C(O)R, —N(OR)S(O)2R, —N(OR)C(O)OR, —N(OR)C(O)N(R)2, —N(OR)C(S)N(R)2, —N(OR)C(═NR9)N(R)2, —N(OR)C(═CHR9)N(R)2, —C(═NR9)N(R)2, —C(═NR9)R, —C(O)N(R)OR, and a 5- to 14-membered heterocycloalkyl having one or more heteroatoms selected from N, O, and S which is substituted with one or more substituents selected from oxo (═O), OH, amino, mono- or di-alkylamino, and C1-3alkyl, and each n is independently selected from 1, 2, 3, 4, and 5;

each R5is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

each R6is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

M and M′ are independently selected from —C(O)O—, —OC(O)—, —C(O)N(R′)—, —N(R′)C(O)—, —C(O)—, —C(S)—, —C(S)S—, —SC(S)—, —CH(OH)—, —P(O)(OR′)O—, —S(O)2—, —S—S—, an aryl group, and a heteroaryl group;

R7is selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

R8is selected from the group consisting of C3-6carbocycle and heterocycle;

R9is selected from the group consisting of H, CN, NO2, C1-6alkyl, —OR, —S(O)2R, —S(O)2N(R)2, C2-6alkenyl, C3-6carbocycle and heterocycle;

each R is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

each R′ is independently selected from the group consisting of C1-8alkyl, C2-18alkenyl, —R*YR″, —YR″, and H;

each R″ is independently selected from the group consisting of C3-14alkyl and C3-14alkenyl;

each R* is independently selected from the group consisting of C1-12alkyl and C2-12alkenyl;

each Y is independently a C3-6carbocycle;

each X is independently selected from the group consisting of F, Cl, Br, and I; and

m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13,

or salts or isomers thereof.

In yet another embodiments, another subset of compounds of Formula (I) includes those in which

R1is selected from the group consisting of C5-30alkyl, C5-20alkenyl, —R*YR″, —YR″, and —R″M′R′;

R2and R3are independently selected from the group consisting of H, C1-14alkyl, C2-14alkenyl, —R*YR″, —YR″, and —R*OR″, or R2and R3, together with the atom to which they are attached, form a heterocycle or carbocycle;

R4is selected from the group consisting of a C3-6carbocycle, —(CH2)nQ, —(CH2)nCHQR, —CHQR, —CQ(R)2, and unsubstituted C1-6alkyl, where Q is selected from a C3-6carbocycle, a 5- to 14-membered heterocycle having one or more heteroatoms selected from N, O, and S, —OR, —O(CH2)nN(R)2, —C(O)OR, —OC(O)R, —CX3, —CX2H, —CXH2, —CN, —C(O)N(R)2, —N(R)C(O)R, —N(R)S(O)2R, —N(R)C(O)N(R)2, —N(R)C(S)N(R)2, —CRN(R)2C(O)OR, —N(R)R8, —O(CH2)nOR, —N(R)C(═NR9)N(R)2, —N(R)C(═CHR9)N(R)2, —OC(O)N(R)2, —N(R)C(O)OR, —N(OR)C(O)R, —N(OR)S(O)2R, —N(OR)C(O)OR, —N(OR)C(O)N(R)2, —N(OR)C(S)N(R)2, —N(OR)C(═NR9)N(R)2, —N(OR)C(═CHR9)N(R)2, —C(═NR9)R, —C(O)N(R)OR, and —C(═NR9)N(R)2, and each n is independently selected from 1, 2, 3, 4, and 5; and when Q is a 5- to 14-membered heterocycle and (i) R4is —(CH2)nQ in which n is 1 or 2, or (ii) R4is —(CH2)nCHQR in which n is 1, or (iii) R4is —CHQR, and —CQ(R)2, then Q is either a 5- to 14-membered heteroaryl or 8- to 14-membered heterocycloalkyl;

each R5is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

each R6is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

M and M′ are independently selected from —C(O)O—, —OC(O)—, —C(O)N(R′)—, —N(R′)C(O)—, —C(O)—, —C(S)—, —C(S)S—, —SC(S)—, —CH(OH)—, —P(O)(OR′)O—, —S(O)2—, —S—S—, an aryl group, and a heteroaryl group;

R7is selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

R8is selected from the group consisting of C3-6carbocycle and heterocycle;

R9is selected from the group consisting of H, CN, NO2, C1-6alkyl, —OR, —S(O)2R, —S(O)2N(R)2, C2-6alkenyl, C3-6carbocycle and heterocycle;

each R is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

each R′ is independently selected from the group consisting of C1-8alkyl, C2-18alkenyl, —R*YR″, —YR″, and H;

each R″ is independently selected from the group consisting of C3-14alkyl and C3-14alkenyl;

each R* is independently selected from the group consisting of C1-12alkyl and C2-12alkenyl;

each Y is independently a C3-6carbocycle;

each X is independently selected from the group consisting of F, Cl, Br, and I; and

m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13,

or salts or isomers thereof.

In still another embodiments, another subset of compounds of Formula (I) includes those in which

R1is selected from the group consisting of C5-30alkyl, C5-20alkenyl, —R*YR″, —YR″, and —R″M′R′;

R2and R3are independently selected from the group consisting of H, C1-14alkyl, C2-14alkenyl, —R*YR″, —YR″, and —R*OR″, or R2and R3, together with the atom to which they are attached, form a heterocycle or carbocycle;

R4is selected from the group consisting of a C3-6carbocycle, —(CH2)nQ, —(CH2)nCHQR, —CHQR, —CQ(R)2, and unsubstituted C1-6alkyl, where Q is selected from a C3-6carbocycle, a 5- to 14-membered heteroaryl having one or more heteroatoms selected from N, O, and S, —OR, —O(CH2)nN(R)2, —C(O)OR, —OC(O)R, —CX3, —CX2H, —CXH2, —CN, —C(O)N(R)2, —N(R)C(O)R, —N(R)S(O)2R, —N(R)C(O)N(R)2, —N(R)C(S)N(R)2, —CRN(R)2C(O)OR, —N(R)R8, —O(CH2)nOR, —N(R)C(═NR9)N(R)2, —N(R)C(═CHR9)N(R)2, —OC(O)N(R)2, —N(R)C(O)OR, —N(OR)C(O)R, —N(OR)S(O)2R, —N(OR)C(O)OR, —N(OR)C(O)N(R)2, —N(OR)C(S)N(R)2, —N(OR)C(═NR9)N(R)2, —N(OR)C(═CHR9)N(R)2, —C(═NR9)R, —C(O)N(R)OR, and —C(═NR9)N(R)2, and each n is independently selected from 1, 2, 3, 4, and 5;

each R5is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

each R6is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

M and M′ are independently selected from —C(O)O—, —OC(O)—, —C(O)N(R′)—, —N(R′)C(O)—, —C(O)—, —C(S)—, —C(S)S—, —SC(S)—, —CH(OH)—, —P(O)(OR′)O—, —S(O)2—, —S—S—, an aryl group, and a heteroaryl group;

R7is selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

R8is selected from the group consisting of C3-6carbocycle and heterocycle;

R9is selected from the group consisting of H, CN, NO2, C1-6alkyl, —OR, —S(O)2R, —S(O)2N(R)2, C2-6alkenyl, C3-6carbocycle and heterocycle;

each R is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

each R′ is independently selected from the group consisting of C1-18alkyl, C2-18alkenyl, —R*YR″, —YR″, and H;

each R″ is independently selected from the group consisting of C3-14alkyl and C3-14alkenyl;

each R* is independently selected from the group consisting of C1-12alkyl and C2-12alkenyl;

each Y is independently a C3-6carbocycle;

each X is independently selected from the group consisting of F, Cl, Br, and I; and

m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13,

or salts or isomers thereof.

In yet another embodiments, another subset of compounds of Formula (I) includes those in which

R1is selected from the group consisting of C5-30alkyl, C5-20alkenyl, —R*YR″, —YR″, and —R″M′R′;

R2and R3are independently selected from the group consisting of H, C2-14alkyl, C2-14alkenyl, —R*YR″, —YR″, and —R*OR″, or R2and R3, together with the atom to which they are attached, form a heterocycle or carbocycle;

R4is —(CH2)nQ or —(CH2)nCHQR, where Q is —N(R)2, and n is selected from 3, 4, and 5;

each R5is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

each R6is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

M and M′ are independently selected from —C(O)O—, —OC(O)—, —C(O)N(R′)—, —N(R′)C(O)—, —C(O)—, —C(S)—, —C(S)S—, —SC(S)—, —CH(OH)—, —P(O)(OR′)O—, —S(O)2—, —S—S—, an aryl group, and a heteroaryl group;

R7is selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

each R is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

each R′ is independently selected from the group consisting of C1-18alkyl, C2-18alkenyl, —R*YR″, —YR″, and H;

each R″ is independently selected from the group consisting of C3-14alkyl and C3-14alkenyl;

each R* is independently selected from the group consisting of C1-12alkyl and C1-12alkenyl;

each Y is independently a C3-6carbocycle;

each X is independently selected from the group consisting of F, Cl, Br, and I; and

m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13,

or salts or isomers thereof.

In still another embodiments, another subset of compounds of Formula (I) includes those in which

R1is selected from the group consisting of C5-30alkyl, C5-20alkenyl, —R*YR″, —YR″, and —R″M′R′;

R2and R3are independently selected from the group consisting of C1-14alkyl, C2-14alkenyl, —R*YR″, —YR″, and —R*OR″, or R2and R3, together with the atom to which they are attached, form a heterocycle or carbocycle;

R4is selected from the group consisting of —(CH2)nQ, —(CH2)nCHQR, —CHQR, and —CQ(R)2, where Q is —N(R)2, and n is selected from 1, 2, 3, 4, and 5;

each R5is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

each R6is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

M and M′ are independently selected from —C(O)O—, —OC(O)—, —C(O)N(R′)—, —N(R′)C(O)—, —C(O)—, —C(S)—, —C(S)S—, —SC(S)—, —CH(OH)—, —P(O)(OR′)O—, —S(O)2—, —S—S—, an aryl group, and a heteroaryl group;

R7is selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

each R is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

each R′ is independently selected from the group consisting of C1-8alkyl, C2-18alkenyl, —R*YR″, —YR″, and H;

each R″ is independently selected from the group consisting of C3-14alkyl and C3-14alkenyl;

each R* is independently selected from the group consisting of C1-12alkyl and C1-12alkenyl;

each Y is independently a C3-6carbocycle;

each X is independently selected from the group consisting of F, Cl, Br, and I; and

m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13,

or salts or isomers thereof.

In certain embodiments, a subset of compounds of Formula (I) includes those of Formula (IA):


or a salt or isomer thereof, wherein 1 is selected from 1, 2, 3, 4, and 5; m is selected from 5, 6, 7, 8, and 9; M1is a bond or M′; R4is unsubstituted C1-3alkyl, or —(CH2)nQ, in which Q is OH, —NHC(S)N(R)2, —NHC(O)N(R)2, —N(R)C(O)R, —N(R)S(O)2R, —N(R)R8, —NHC(═NR9)N(R)2, —NHC(═CHR9)N(R)2, —OC(O)N(R)2, —N(R)C(O)OR, heteroaryl or heterocycloalkyl; M and M′ are independently selected
from —C(O)O—, —OC(O)—, —C(O)N(R′)—, —P(O)(OR′)O—, —S—S—, an aryl group, and a heteroaryl group; and R2and R3are independently selected from the group consisting of H, C1-14alkyl, and C2-14alkenyl.

In certain embodiments, a subset of compounds of Formula (I) includes those of Formula (II):


R3(II) or a salt or isomer thereof, wherein 1 is selected from 1, 2, 3, 4, and 5; M1is a bond or M′; R4is unsubstituted C1-3alkyl, or —(CH2)nQ, in which n is 2, 3, or 4, and Q is OH, —NHC(S)N(R)2, —NHC(O)N(R)2, —N(R)C(O)R, —N(R)S(O)2R, —N(R)R8, —NHC(═NR9)N(R)2, —NHC(═CHR9)N(R)2, —OC(O)N(R)2, —N(R)C(O)OR, heteroaryl or heterocycloalkyl; M and M′ are independently selected
from —C(O)O—, —OC(O)—, —C(O)N(R′)—, —P(O)(OR′)O—, —S—S—, an aryl group, and a heteroaryl group; and R2and R3are independently selected from the group consisting of H, C1-14alkyl, and C2-14alkenyl.

In certain embodiments, a subset of compounds of Formula (I) includes those of Formula (IIa), (IIb), (IIc), or (IIe):


or a salt or isomer thereof, wherein R4is as described herein.

In certain embodiments, a subset of compounds of Formula (I) includes those of Formula (IId):


or a salt or isomer thereof, wherein n is 2, 3, or 4; and m, R′, R″, and R2through R6are as described herein. For example, each of R2and R3may be independently selected from the group consisting of C5-14alkyl and C5-14alkenyl.

In another aspect, the disclosure features a nanoparticle composition including a lipid component comprising a compound as described herein (e.g., a compound according to Formula (I), (IA), (II), (IIa), (IIb), (IIc), (IId) or (IIe)).

In yet another aspect, the disclosure features a pharmaceutical composition comprising a nanoparticle composition according to the preceding aspects and a pharmaceutically acceptable carrier. For example, the pharmaceutical composition is 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.). For example, the pharmaceutical composition is a solution that is refrigerated for storage and/or shipment at, for example, about −20° C., −30° C., −40° C., −50° C., −60° C., −70° C., or −80° C.

In another aspect, the disclosure provides a method of delivering a therapeutic and/or prophylactic (e.g., an mRNA) to a cell (e.g., a mammalian cell). This method includes the step of administering to a subject (e.g., a mammal, such as a human) a nanoparticle composition including (i) a lipid component including a phospholipid (such as a polyunsaturated lipid), a PEG lipid, a structural lipid, and a compound of Formula (I), (IA), (II), (IIa), (IIb), (IIc), (IId) or (IIe) and (ii) a therapeutic and/or prophylactic, in which administering involves contacting the cell with the nanoparticle composition, whereby the therapeutic and/or prophylactic is delivered to the cell.

In another aspect, the disclosure provides a method of producing a polypeptide of interest in a cell (e.g., a mammalian cell). The method includes the step of contacting the cell with a nanoparticle composition including (i) a lipid component including a phospholipid (such as a polyunsaturated lipid), a PEG lipid, a structural lipid, and a compound of Formula (I), (IA), (II), (IIa), (IIb), (IIc), (IId) or (IIe) and (ii) an mRNA encoding the polypeptide of interest, whereby the mRNA is capable of being translated in the cell to produce the polypeptide.

In another aspect, the disclosure provides a method of treating a disease or disorder in a mammal (e.g., a human) in need thereof. The method includes the step of administering to the mammal a therapeutically effective amount of a nanoparticle composition including (i) a lipid component including a phospholipid (such as a polyunsaturated lipid), a PEG lipid, a structural lipid, and a compound of Formula (I), (IA), (II), (IIa), (IIb), (IIc), (IId) or (IIe) and (ii) a therapeutic and/or prophylactic (e.g., an mRNA). In some embodiments, the disease or disorder is characterized by dysfunctional or aberrant protein or polypeptide activity. For example, the disease or disorder is selected from the group consisting of rare diseases, infectious diseases, cancer and proliferative diseases, genetic diseases (e.g., cystic fibrosis), autoimmune diseases, diabetes, neurodegenerative diseases, cardio- and reno-vascular diseases, and metabolic diseases.

In another aspect, the disclosure provides a method of delivering (e.g., specifically delivering) a therapeutic and/or prophylactic to a mammalian organ (e.g., a liver, spleen, lung, or femur). This method includes the step of administering to a subject (e.g., a mammal) a nanoparticle composition including (i) a lipid component including a phospholipid, a PEG lipid, a structural lipid, and a compound of Formula (I), (IA), (II), (IIa), (IIb), (IIc), (IId) or (IIe) and (ii) a therapeutic and/or prophylactic (e.g., an mRNA), in which administering involves contacting the cell with the nanoparticle composition, whereby the therapeutic and/or prophylactic is delivered to the target organ (e.g., a liver, spleen, lung, or femur).

In another aspect, the disclosure features a method for the enhanced delivery of a therapeutic and/or prophylactic (e.g., an mRNA) to a target tissue (e.g., a liver, spleen, lung, or femur). This method includes administering to a subject (e.g., a mammal) a nanoparticle composition, the composition including (i) a lipid component including a compound of Formula (I), (IA), (II), (IIa), (IIb), (IIc), (IId) or (IIe), a phospholipid, a structural lipid, and a PEG lipid; and (ii) a therapeutic and/or prophylactic, the administering including contacting the target tissue with the nanoparticle composition, whereby the therapeutic and/or prophylactic is delivered to the target tissue.

In yet another aspect, the disclosure features a method of lowering immunogenicity comprising introducing the nanoparticle composition of the disclosure into cells, wherein the nanoparticle composition reduces the induction of the cellular immune response of the cells to the nanoparticle composition, as compared to the induction of the cellular immune response in cells induced by a reference composition which comprises a reference lipid instead of a compound of Formula (I), (IA), (II), (IIa), (IIb), (IIc), (IId) or (IIe). For example, the cellular immune response is an innate immune response, an adaptive immune response, or both.

The disclosure also includes methods of synthesizing a compound of Formula (I), (IA), (II), (IIa), (IIb), (IIc), (IId) or (IIe) and methods of making a nanoparticle composition including a lipid component comprising the compound of Formula (I), (IA), (II), (IIa), (IIb), (IIc), (IId) or (IIe).

