COMPOUNDS AND COMPOSITIONS FOR DELIVERY OF THERAPEUTIC AGENTS

1 . A cationic lipid of Formula (I):

or an isomer thereof, wherein:

R′x is:

 R′ y is:

 and R′ z is:

wherein

 denotes a point of attachment;

R xα , R xγ , R xγ , and R xδ are each independently selected from the group consisting of H, C 1-12 alkyl, and C 2-12 alkenyl;

R yα , R yβ , R yγ , and R yδ are each independently selected from the group consisting of H, C 1-12 alkyl, and C 2-12 alkenyl;

R zα , R zβ , R zγ , and R zδ are each independently selected from the group consisting of H, C 1-12 alkyl, and C 2-12 alkenyl;

R H is —(CH 2 ) q OH, wherein q is selected from 1, 2, 3, 4, and 5;

each R T is independently selected from C 1-12 alkyl and C 2-12 alkenyl;

a is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9;

b is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9;

c is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9; and

A − is any pharmaceutically acceptable anion.

2 . The cationic lipid of claim 1 , wherein

R′ x is

 R′ y is:

 and

R′ z is:

wherein

 denotes a point of attachment;

R xγ is selected from the group consisting of H, C 1-12 alkyl, and C 2-12 alkenyl;

R yγ is selected from the group consisting of H, C 1-12 alkyl, and C 2-12 alkenyl;

R zγ is selected from the group consisting of H, C 1-12 alkyl, and C 2-12 alkenyl; and

R 2a , R 2b , R 2c , R 3a , R 3b , and R 3c are each independently selected from the group consisting of C 1-14 alkyl and C 2-14 alkenyl.

3 . The cationic lipid of claim 1 , wherein

R′ a is:

 R′ b is:

 and R′ c is:

wherein

 denotes a point of attachment;

R′ xγ is selected from the group consisting of H, C 1-12 alkyl, and C 2-12 alkenyl;

R yγ is selected from the group consisting of H, C 1-12 alkyl, and C 2-12 alkenyl; and

R 2c and R 3c are each independently selected from the group consisting of C 1-14 alkyl and C 2-14 alkenyl.

4 . The compound of any one of claims 1-3 , wherein R xγ and R yγ are each H.

5 . The compound of any one of claims 1-3 , wherein R xγ and R yγ are each C 1-12 alkyl or C 2 -12 alkenyl.

6 . The compound of any one of claims 1-3 , wherein R 7 is C 1-12 alkyl or C 2-12 alkenyl and R yγ is H.

7 . The compound of any one of the preceding claims , wherein q is 2.

8 . The compound of any one of claims 1-3 , wherein the compound is selected from:

9 . The compound of any one of the preceding claims , wherein A − is selected from chloride, bromide, iodide, hydroxide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate.

10 . The compound of any one of the preceding claims , wherein A − is selected from bromide, chloride, and hydroxide.

11 . An empty lipid nanoparticle (empty LNP) comprising a cationic lipid of any one of the preceding claims .

12 . The empty LNP of claim 11 , wherein the empty LNP further comprises an ionizable lipid.

13 . The empty LNP of claim 11 or 12 , wherein the empty LNP further comprises a phospholipid.

14 . The empty LNP of any one of claims 11-13 , wherein the empty LNP further comprises a structural lipid.

15 . The empty LNP of any one of claims 11-14 , wherein the empty LNP further comprises a PEG lipid.

16 . A empty LNP comprising a lipid component which comprises from about 20 mol % to about 40 mol % of the compound of any one of claims 1-10 ; from about 15 mol % to about 40 mol % ionizable lipid, from about 0 mol % to about 30 mol % phospholipid, from about 15 mol % to about 50 mol % structural lipid, and from about 0 mol % to about 1 mol % PEG lipid.

17 . A loaded lipid nanoparticle (loaded LNP) comprising the empty LNP of any one of claims 11-16 and a therapeutic and/or prophylactic agent.

18 . A loaded LNP comprising:

(a) a loaded LNP core comprising:

(i) an ionizable lipid,

(ii) a phospholipid,

(iii) a structural lipid, and

(iv) a PEG-lipid, and

(b) a therapeutic and/or prophylactic agent encapsulated within the core for delivery into a cell, and

(c) a cationic agent, wherein the cationic agent is a cationic lipid of any one of claims 1-10 .

19 . A loaded LNP comprising:

(a) a loaded LNP core comprising:

(i) an ionizable lipid,

(ii) a phospholipid,

(iii) a structural lipid, and

(iv) a PEG-lipid, and

(b) a therapeutic and/or prophylactic agent encapsulated within the core for delivery into a cell, and

(c) a cationic agent.

20 . The loaded LNP of claim 19 , wherein the cationic agent is a cationic lipid.

21 . The loaded LNP of any one of claims 17-20 , wherein the therapeutic and/or prophylactic agent is a nucleic acid.

22 . The loaded LNP of claim 21 , wherein the therapeutic and/or prophylactic agent is a ribonucleic acid (RNA).

23 . The loaded LNP of claim 22 , wherein the RNA is selected from the group consisting of a short interfering RNA (siRNA), an asymmetrical interfering RNA (aiRNA), a RNA interference (RNAi) molecule, a microRNA (miRNA), an antagomir, an antisense RNA, a ribozyme, a Dicer substrate RNA (dsRNA), a small hairpin RNA (shRNA), a messenger RNA (mRNA), and mixtures thereof.

24 . The loaded LNP of claim 23 , wherein the RNA is an mRNA.

25 . The loaded LNP of claim 24 , wherein the mRNA is a modified mRNA (mmRNA).

26 . The loaded LNP of claim 24 or 25 , wherein the mRNA incorporates a micro-RNA binding site (miR binding site).

27 . The loaded LNP of any one of claims 24-26 , wherein the mRNA includes one or more of a stem loop, a chain terminating nucleoside, a polyA sequence, a polyadenylation signal, and/or a 5′ cap structure.

28 . The empty LNP or loaded LNP of any one of claims 12-27 , wherein the ionizable lipid is a compound of Formula (IL-A):

or its N-oxide, or a salt or isomer thereof, wherein:

R 1 is selected from the group consisting of C 5-30 alkyl, C 5-20 alkenyl, —R*YR″, —YR″, and —R″M′R′;

R 2 and R 3 are independently selected from the group consisting of H, C 1-14 alkyl, C 2-14 alkenyl, —R*YR″, —YR″, and —R*OR″, or R 2 and R 3 , together with the atom to which they are attached, form a heterocycle or carbocycle;

R 4 is selected from the group consisting of hydrogen, a C 3-6 carbocycle, —(CH 2 ) n Q, —(CH 2 ) n CHQR, —(CH 2 ) o C(R 12 ) 2 (CH 2 ) n-o Q, —CHQR, —CQ(R) 2 , —C(O)NQR and unsubstituted C 1-6 alkyl, where Q is selected from a carbocycle, heterocycle, —OR, —O(CH 2 ) n N(R) 2 , —C(O)OR, —OC(O)R, —OC(O)O—, —CX 3 , —CX 2 H, —CXH 2 , —CN, —N(R) 2 , —C(O)N(R) 2 , —N(R)C(O)R, —N(R)S(O) 2 R, —N(R)C(O)N(R) 2 , —N(R)C(S)N(R) 2 , —N(R)R′, —N(R)S(O) 2 R 8 , —O(CH 2 ) n OR, —N(R)C(═NR 9 )N(R) 2 , —N(R)C(═CHR 9 )N(R) 2 , —OC(O)N(R) 2 , —N(R)C(O)OR, —N(OR)C(O)R, —N(OR)S(O) 2 R, —N(OR)C(O)OR, —N(OR)C(O)N(R) 2 , —N(OR)C(S)N(R) 2 , —N(OR)C(═NR 9 )N(R) 2 , —N(OR)C(═CHR 9 )N(R) 2 , —C(═NR 9 )N(R) 2 , —C(═NR 9 )R, —C(O)N(R)OR, —(CH 2 ) n N(R) 2 and —C(R)N(R) 2 C(O)OR, NR A S(O) 2 R SX , and

 wherein A is a 3-14 membered heterocycle containing one or more heteroatoms selected from N, O and S; and a is 1, 2, 3, or 4; wherein

 denotes a point of attachment;

each o is independently selected from 1, 2, 3, and 4, and each n is independently selected from 1, 2, 3, 4, and 5;

R 8 is selected from the group consisting of C 3-6 carbocycle and heterocycle;

R 9 is selected from the group consisting of H, CN, NO 2 , C 1-6 alkyl, —OR, —S(O) 2 R, —S(O) 2 N(R) 2 , C 2-6 alkenyl, C 3-6 carbocycle and heterocycle;

R 12 is selected from the group consisting of H, OH, C 1-3 alkyl, and C 2-3 alkenyl;

each R is independently selected from the group consisting of C 1-6 alkyl, C 1-3 alkyl-aryl, C 2-3 alkenyl, and H;

R A is selected from H and C 1-3 alkyl;

R SX is selected from a C 3-8 carbocycle, a 3-14 membered heterocycle containing one or more heteroatoms selected from N, O and S, C 1-6 alkyl, C 2-6 alkenyl, (C 1-3 alkoxy)C 1-3 alkyl, (CH 2 ) p1 O(CH 2 ) p2 R SX1 , and (CH 2 ) p1 R SX1 , wherein the carbocycle and heterocycle are optionally substituted with one or more groups selected from oxo, C 1-6 alkyl, and (C 1-3 alkoxy)C 1-3 alkyl;

R SX1 is selected from C(O)NR 14 R 14′ , a C 3-8 carbocycle, and a 3-14 membered heterocycle containing one or more heteroatoms selected from N, O and S, wherein the carbocycle and heterocycle are each optionally substituted with one or more groups selected from oxo, halo, C 1-3 alkyl, (C 1-3 alkoxy)C 1-3 alkyl, C 1-6 alkylamino, di-(C 1-6 alkyl) amino, and NH 2 ;

each R 13 is selected from the group consisting of OH, oxo, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 1-6 alkylamino, di-(C 1-6 alkyl) amino, NH 2 , C(O)NH 2 , CN, and NO 2 ;

R 14 and R 14′ are each independently selected from the group consisting of H and C 1-6 alkyl;

p 1 is selected from 1, 2, 3, 4, and 5;

p 2 is selected from 1, 2, 3, 4, and 5;

each R 5 is independently selected from the group consisting of OH, C 1-3 alkyl, C 2-3 alkenyl, and H;

each R 6 is independently selected from the group consisting of OH, C 1-3 alkyl, C 2-3 alkenyl, and H;

R 7 is selected from the group consisting of C 1-3 alkyl, C 2-3 alkenyl, and H;

M and M′ are independently selected from —C(O)O—, —OC(O)—, —OC(O)O—, —OC(O)-M″-C(O)O—, —C(O)N(R M )—, —N(R M )C(O)—, —C(O)—, —C(S)—, —C(S)S—, —SC(S)—, —CH(OH)—, —P(O)(O R M )O—, —S(O) 2 —, —S—S—, an aryl group, and a heteroaryl group, in which M″ is a bond, C 1-13 alkyl or C 2-13 alkenyl;

each R M is independently selected from the group consisting of H, C 1-6 alkyl and C 2-6 alkenyl;

each R′ is independently selected from the group consisting of C 1-18 alkyl, C 2-18 alkenyl, —R*YR″, —YR″, (CH 2 ) q′ OR*, and H,

and each q′ is independently selected from 1, 2, and 3;

each R″ is independently selected from the group consisting of C 3-15 alkyl and C 3-15 alkenyl;

each R* is independently selected from the group consisting of C 1-12 alkyl and C 2-12 alkenyl;

each Y is independently a C 3-6 carbocycle;

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.

29 . The empty LNP or loaded LNP of claim 28 , wherein the ionizable lipid is a compound of Formula (IL-B):

or its N-oxide, or a salt or isomer thereof, wherein:

R′ a is R′ branched ; wherein R′ branched is:

 wherein

 denotes a point of attachment;

wherein R aα , R aβ , R aγ , and R aδ are each independently selected from the group consisting of H, C 2-12 alkyl, and C 2-12 alkenyl;

R 2 and R 3 are each independently selected from the group consisting of C 1-14 alkyl and C 2-14 alkenyl;

R 4 is selected from the group consisting of —(CH 2 ) n OH, wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, and

wherein

 denotes a point of attachment; wherein

R 10 is N(R) 2 ; each R is independently selected from the group consisting of C 1-6 alkyl, C 2-3 alkenyl, and H; and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

each R 5 is independently selected from the group consisting of C 1-3 alkyl, C 2-3 alkenyl, and H;

each R 6 is independently selected from the group consisting of C 1-3 alkyl, C 2-3 alkenyl, and H;

M and M′ are each independently selected from the group consisting of —C(O)O— and —OC(O)—;

R′ is a C 1-12 alkyl or C 2-12 alkenyl;

l is selected from the group consisting of 1, 2, 3, 4, and 5; and

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

30 . The empty LNP or loaded LNP of claim 28 , wherein the ionizable lipid is a compound of Formula (TL-C):

or a salt or isomer thereof, wherein

l is selected from 1, 2, 3, 4, and 5;

M 1 is M′;

R 4 is —(CH 2 ) n Q, in which Q is OH, and n is selected from 1, 2, 3, 4, or 5;

M and M′ are independently selected from —C(O)O—, and —OC(O)—;

R 2 and R 3 are both C 1-14 alkyl, or C 2-14 alkenyl; and

R′ is a C 1 -C 12 linear alkyl.

31 . The empty LNP or loaded LNP of claim 28 , wherein the ionizable lipid is a compound of Formula (IL-D):

or its N-oxide, or a salt or isomer thereof,

wherein R′ a is R′ branched or R′ cyclic ; wherein

R′ branched is

 and R′b is:

wherein

 denotes a point of attachment;

wherein R aγ is selected from the group consisting of C 1-12 alkyl and C 2-12 alkenyl;

R 2 and R 3 are each independently selected from the group consisting of C 1-14 alkyl and C 2-14 alkenyl;

R 4 is —(CH 2 ) n OH wherein n is selected from the group consisting of 1, 2, 3, 4, and 5;

R′ is a C 1-12 alkyl or C 2-12 alkenyl;

m is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9;

l is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9.

32 . The empty LNP or loaded LNP of any one of claims 12-27 , wherein the ionizable lipid is a compound of Formula (IL-III):

or a salt or isomers thereof, wherein,

W is

ring A is

t is 1 or 2;

A 1 and A 2 are each independently selected from CH or N;

Z is CH 2 or absent wherein when Z is CH 2 , the dashed lines (1) and (2) each represent a single bond; and when Z is absent, the dashed lines (1) and (2) are both absent;

R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of C 5-20 alkyl, C 5-20 alkenyl, —R″MR′, —R*YR″, —YR″, and —R*OR″;

R X1 and R X2 are each independently H or C 1-3 alkyl;

each M is independently selected from the group consisting of —C(O)O—, —OC(O)—, —OC(O)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 —, —C(O)S—, —SC(O)—, an aryl group, and a heteroaryl group;

M* is C 1 -C 6 alkyl,

W 1 and W 2 are each independently selected from the group consisting of —O— and —N(R 6 )—;

each R 6 is independently selected from the group consisting of H and C 1-5 alkyl;

X 1 , X 2 , and X 3 are independently selected from the group consisting of a bond, —CH 2 —, —(CH 2 ) 2 —, —CHR—, —CHY—, —C(O)—, —C(O)O—, —OC(O)—, —(CH 2 ) n —C(O)—, —C(O)—(CH 2 ) n —, —(CH 2 ) n —C(O)O—, —OC(O)—(CH 2 ) n —, —(CH 2 ) n —OC(O)—, —C(O)O—(CH 2 ) n —, —CH(OH)—, —C(S)—, and —CH(SH)—;

each Y is independently a C 3-6 carbocycle;

each R* is independently selected from the group consisting of C 1-12 alkyl and C 2-12 alkenyl;

each R is independently selected from the group consisting of C 1-3 alkyl and a C 3-6 carbocycle;

each R′ is independently selected from the group consisting of C 1-12 alkyl, C 2-12 alkenyl, and H;

each R″ is independently selected from the group consisting of C 3-12 alkyl, C 3-12 alkenyl and —R*MR′; and

n is an integer from 1-6.

33 . The empty LNP or loaded LNP of claim 32 , wherein the ionizable lipid is a compound of Formula (IL-IIIA):

or a salt or isomer thereof, wherein

R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of C 5-20 alkyl, C 5-20 alkenyl, —R″MR′, —R*YR″, —YR″, and —R*OR″;

each M is independently selected from the group consisting of —C(O)O—, —OC(O)—, —OC(O)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 —, an aryl group, and a heteroaryl group;

X 1 , X 2 , and X 3 are independently selected from the group consisting of a bond, —CH 2 —, —(CH 2 ) 2 —, —CHR—, —CHY—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)—CH 2 —, —CH 2 —C(O)—, —C(O)O—CH 2 —, —OC(O)—CH 2 —, —CH 2 —C(O)O—, —CH 2 —OC(O)—, —CH(OH)—, —C(S)—, and —CH(SH)—;

each Y is independently a C 3-6 carbocycle;

each R* is independently selected from the group consisting of C 1-12 alkyl and C 2-12 alkenyl;

each R is independently selected from the group consisting of C 1-3 alkyl and a C 3-6 carbocycle;

each R′ is independently selected from the group consisting of C 1-12 alkyl, C 2-12 alkenyl, and H; and

each R″ is independently selected from the group consisting of C 3-12 alkyl and C 3-12 alkenyl.

34 . The empty LNP or loaded LNP of claim 32 or 33 , wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each C 5-20 alkyl; X 1 is —CH 2 —; and X 2 and X 3 are each —C(O)—.

35 . The empty LNP or loaded LNP of any one of claims 12-27 , wherein the ionizable lipid is a compound selected from:

36 . The empty LNP or loaded LNP of any one of claims 12-27 , wherein the ionizable lipid is a compound selected from the compounds of Tables IL-1 to TL-7.

37 . The empty LNP or loaded LNP of any one of claims 13-36 , wherein the phospholipid is selected from the group consisting of

1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC),

1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC),

1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC),

1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC),

1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC),

1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC),

1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC),

1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC),

1-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC),

1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC),

1,2-dilinolenoyl-sn-glycero-3-phosphocholine,

1,2-diarachidonoyl-sn-glycero-3-phosphocholine,

1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine,

1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE),

1,2-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,

1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine,

1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine,

1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG),

dipalmitoylphosphatidylglycerol (DPPG), palmitoyloleoylphosphatidylethanolamine (POPE),

distearoyl-phosphatidyl-ethanolamine (DSPE),

dipalmitoyl phosphatidyl ethanolamine (DPPE),

dimyristoylphosphoethanolamine (DMPE),

1-stearoyl-2-oleoyl-phosphatidyethanolamine (SOPE),

1-stearoyl-2-oleoyl-phosphatidylcholine (SOPC),

sphingomyelin, phosphatidylcholine, phosphatidylethanolamine,

phosphatidylserine,

phosphatidylinositol,

phosphatidic acid,

palmitoyloleoyl phosphatidylcholine,

lysophosphatidylcholine,

lysophosphatidylethanolamine (LPE)

sphingomyelin, and

mixtures thereof.

38 . The empty LNP or loaded LNP of claim 37 , wherein the phospholipid is DSPC.

39 . The empty LNP or loaded LNP of any one of claims 14-38 , wherein the structural lipid is selected from the group consisting of cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, alpha-tocopherol, and mixtures thereof.

40 . The empty LNP or loaded LNP of claim 39 , wherein the structural lipid is

or a salt thereof.

41 . The empty LNP or loaded LNP of any one of claims 15-40 , wherein the PEG lipid is selected from the group consisting of a PEG-modified phosphatidylethanolamine, a PEG-modified phosphatidic acid, a PEG-modified ceramide, a PEG-modified dialkylamine, a PEG-modified diacylglycerol, a PEG-modified dialkylglycerol, and mixtures thereof.

42 . The empty LNP or loaded LNP of claim 41 , wherein the PEG lipid is a compound of one of the following structures:

or a salt thereof, wherein r is an integer from 1 to 100; and s is an integer from 1 to 100.

43 . The empty LNP or loaded LNP of claim 42 , wherein the PEG lipid is one of the following compounds:

or a salt thereof.

44 . A pharmaceutical composition comprising the loaded LNP of any one of claims 17-43 and a pharmaceutically acceptable carrier.

45 . A method of delivering a therapeutic and/or prophylactic agent to a cell within a subject, the method comprising administering to the subject the loaded LNP of any one of claims 17-43 , or a pharmaceutical composition of claim 44 .

46 . A method of producing a polypeptide of interest in a cell within a subject, the method comprising administering to the subject the loaded LNP of any one of claims 17-43 , or a pharmaceutical composition of claim 44 .

47 . The method of claim 45 or 46 , wherein the cell is an endothelial cell.

48 . The method of claim 47 , wherein the endothelial cell is a pulmonary endothelial cell, a respiratory endothelial cell, or a bronchial endothelial cell.

49 . A method of specifically delivering a therapeutic and/or prophylactic agent to an organ of a subject, the method comprising administering to the subject the loaded LNP of any one of claims 17-43 , or a pharmaceutical composition of claim 44 .

50 . The method of claim 49 , wherein the organ is the lung.

51 . A method of specifically delivering a therapeutic and/or prophylactic agent to a tissue of a subject, the method comprising administering to the subject the loaded LNP of any one of claims 17-43 , or a pharmaceutical composition of claim 44 .

52 . The method of claim 51 , wherein the tissue is the endothelium.

53 . The method of claim 51 , wherein the tissue is the pulmonary endothelium.

54 . 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 loaded LNP of any one claims 17-43 , or a pharmaceutical composition of claim 44 .

55 . The method of any one of claims 45-54 , wherein the administering is performed parenterally, intramuscularly, intradermally, subcutaneously, and/or intravenously.