Composition comprising selective organ targeting lipids

Abstract

The present invention relates to a composition in which a selective organ targeting lipid (SORT lipid) is added to lipid nanoparticles (LNP), which can accurately deliver therapeutic molecules to specific tissues, particularly the spleen or immune cells. The composition exhibits excellent delivery efficiency and in vivo stability, and thus can be advantageously applied in the technical field related to nucleic acid therapeutic agents.

Description

Composition containing selective long-term target lipids

[0001] The present invention relates to a composition comprising a selective organ-targeting lipid capable of controllingly delivering nucleic acids to a target tissue. More specifically, the present invention relates to a composition comprising a selective organ-targeting lipid that targets the spleen or immune cells.

[0002] Although active research is being conducted to prevent or treat diseases by delivering nucleic acids into the body, such as RNA inhibitors, antisense oligonucleotides (ASOs), short interfering RNA (siRNA), aptamers, messenger RNA (mRNA), self-amplifying RNA (SAM), and circular RNA, nucleic acids have the disadvantage of being easily degraded in the blood by enzymes in the body, such as RNase and nuclease. Furthermore, among nucleic acids, mRNA, which has a long length of more than 500 nucleotides, has a large molecular weight of more than 200 kDa, making it difficult to deliver nucleic acids to target cells in the body, and the negative charge of nucleic acids is a factor that hinders the delivery of nucleic acids to target cells in the body.

[0003] Accordingly, the importance of lipid nanoparticles (LNPs) is increasing as drug delivery systems designed to safely deliver nucleic acids to target cells or tissues by stably delivering them into the body while preventing degradation by endogenous enzymes. Lipid nanoparticles contribute to delivering nucleic acids into cells by penetrating the cell membrane; recently, mRNA-based COVID-19 vaccines (Spikevax TM , Comirnaty TM Lipid nanoparticles were also used in the development process.

[0004] However, while lipid nanoparticles are a clinically safe and effective mature technology for delivering genetic medicines, intravenously administered lipid nanoparticles generally accumulate in the liver and target hepatocytes, severely limiting their therapeutic application; therefore, the development of nucleic acid delivery systems capable of extrahepatic targeting is necessary.

[0005] Conventional lipid nanoparticles consist of a total of four lipids: ionizable lipid, phospholipid, cholesterol, and PEG-lipid. It is known that adding a fifth component (Selective Organ Targeting lipid, SORT lipid) to the existing four components for mRNA delivery to the liver alters the in vivo organ targeting characteristics of lipid nanoparticles, resulting in mRNA delivery to tissues other than the liver. Phosphate lipids, which carry a negative charge, are representative Selective Organ Targeting lipids for spleen delivery.

[0006] [Prior Art Literature]

[0007] [Patent Literature]

[0008] (Patent Document 1) Korean Patent Publication No. 10-2024-0006456 (January 15, 2024)

[0009] The object of the present invention is to provide a composition comprising a selective organ target lipid that is a lipid not containing a phosphate group, is zwitterionic, has a carboxyl group, or carries a positive or negative charge, for targeted delivery to the spleen or immune cells (immune cell, macrophage, DC cell, T cell, neutrophil, eosinophil, NK cell, etc.).

[0010] According to the first aspect of the present invention,

[0011] The present invention provides a composition comprising ionizable lipid; selective organ targeting lipid; cholesterol; and PEG lipid (polyethylene glycol lipid).

[0012] In one embodiment of the present invention, the composition may further include a helper lipid.

[0013] In one embodiment of the present invention, the ionized lipid may include 1 to 10 nitrogen atoms and 1 to 10 biodegradable bonds.

[0014] In one embodiment of the present invention, the ionized lipid comprises a pyrazole structure or a diazabicyclo structure and may comprise 1 to 10 ester bonds.

[0015] In one embodiment of the present invention, the ionized lipid may be selected from the group consisting of the following:

[0016] (1) bis(2-propylhexyl)6,6'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))dihexanoate;

[0017] (2) bis(2-propylhexyl)8,8'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))dioctanoate;

[0018] (3) bis(2-ethylpentyl)4,4'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))dibutyrate;

[0019] (4) bis(2-ethylpentyl)6,6'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))dihexanoate;

[0020] (5) bis(2-ethylpentyl)8,8'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))dioctanoate;

[0021] (6) (((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(methylene))bis(propane-2,1,3-triyl)tetrahexanoate;

[0022] (7) (((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(methylene))bis(propane-2,1,3-triyl)tetraoctanoate;

[0023] (8) (((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(methylene))bis(propane-2,1,3-triyl) tetrakis(decanoate);

[0024] (9) di(henicosan-10-yl)3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)methyl)azandyl)dipropionate;

[0025] (10) di(pentadecan-7-yl)3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)dipropionate;

[0026] (11) 1,1'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(tetradecane-2-ol);

[0027] (12) (((1-(2-(bis(6-((2-hexyldecanoyl)oxy)hexyl)amino)ethyl)-1H-pyrazole-4-yl)methyl)azandil)bis(hexane-6,1-diyl)bis(2-hexyldecanoate);

[0028] (13) di((Z)-non-2-en-1-yl)9,9'-(((1-(2-(bis(9-(((Z)-non-2-en-1-yl)oxy)-9-oxononyl)amino)ethyl)-1H-pyrazol-4-)methyl)azandyl)dinonanoate;

[0029] (14) N-((1-(2-(ditetradecylamino)ethyl)-1H-pyrazol-4-yl)methyl)-N-trade

[0030] Siltetradecane-1-amine;

[0031] (15) (((((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(ethane-2,1-diyl))bis(azantryl))tetrakis(hexane-6,1-diyl)tetrakis(2-hexyldecanoate);

[0032] (16) (((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)azandil)bis(hexane-6,1-diyl)bis(2-hexyldecanoate);

[0033] (17) di(pentadecan-7-yl)6,6'-(((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)azandyl)dihexanoate;

[0034] (18) (((((1-(2-hydroxyethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(ethane-2,1-diyl))bis(azantryl))tetrakis(hexane-6,1-diyl)tetrakis(2-hexyldecanoate);

[0035] (19) (((((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(ethane-2,1-diyl))bis(azantryl))tetrakis(hexane-6,1-diyl)tetrakis(2-hexyldecanoate);

[0036] (20) di((Z)-non-2-en-1-yl)9,9'-(((1-(2-(bis(2-hydroxyethyl)amino)ethyl)-1H-pyrazol-4-yl)methyl)azandyl)dinonanoate;

[0037] (21) didodecyl 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)dipropionate;

[0038] (22) Didodecyl 3,3'-(((1-(2-hydroxyethyl)-1H-pyrazole-4-yl)methyl)azandyl)dipropionate;

[0039] (23) didodecyl 3,3'-(((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)azandiyl)dipropionate;

[0040] (24) 11-((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)-24-hexyl-8,14,23-trioxo-7,15,22-trioxa-11-azadotriacontyl 2-hexyl undecanoate;

[0041] (25) 24-hexyl-11-((1-(2-hydroxyethyl)-1H-pyrazole-4-yl)methyl)-8,14,23-trioxo-7,15,22-trioxa-11-azadotriacontyl 2-hexyl undecanoate;

[0042] (26) 24-hexyl-11-((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)-8,14,23-trioxo-7,15,22-trioxa-11-azadotriacontyl 2-hexyl undecanoate;

[0043] (27) Dioctyl 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)methyl)azandyl)dipropionate;

[0044] (28) Dihexadecyl 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)dipropionate;

[0045] (29) ((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(butane-4,1-diyl)bis(2-hexyldecanoate);

[0046] (30) di((Z)-non-2-en-1-yl) 9,9'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)dinonanoate;

[0047] (31) di((Z)-non-2-en-1-yl) 9,9'-(((1-(2-hydroxyethyl)-1H-pyrazole-4-yl)methyl)azandyl)dinonanoate;

[0048] (32) di((Z)-non-2-en-1-yl) 9,9'-(((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)azandyl)dinonanoate;

[0049] (33) bis(4-(propionyloxy)butyl) 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl) dipropionate;

[0050] (34) ((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(butane-4,1-diyl)dipentanoate;

[0051] (35) ((3,3'-(((1-(2-(dimethylamino)ethyl)- 1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(butane-4,1-diyl) diheptanoate;

[0052] (36) ((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(butane-4,1-diyl)dinonanoate;

[0053] (37) ((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(butane-4,1-diyl) diundecanoate;

[0054] (38) ((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(ethane-2,1-diyl) diheptanoate;

[0055] (39) ((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(propane-3,1-diyl)dihexanoate;

[0056] (40) ((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandil)bis(propanoyl))bis(oxy))bis(pentane-5,1-diyl)dibutyrate;

[0057] (41) bis(2-ethylhexyl)4,4'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandil)bis(propanoyl))bis(oxy))dibutyrate;

[0058] (42) bis(2-ethylhexyl)6,6'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandil)bis(propanoyl))bis(oxy))dihexanoate;

[0059] (43) bis(2-ethylhexyl)8,8'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandil)bis(propanoyl))bis(oxy))dioctanoate;

[0060] (44) bis(2-propylhexyl)4,4'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))dibutyrate;

[0061] (45) (2R,2'R)-1,1'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandiyl)bis(decan-2-ol);

[0062] (46) (S)-1-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)((R)-2-hydroxydecyl)amino)decane-2-ol;

[0063] (47) (2R,2'R)-1,1'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandiyl)bis(dodecane-2-ol);

[0064] (48) (S)-1-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)((R)-2-hydroxydodecyl)amino)dodecane-2-ol;

[0065] (49) (2R,2'R)-1,1'-(((1-(2-hydroxyethyl)-1H-pyrazole-4-yl)methyl)azandiyl)bis(dodecane-2-ol);

[0066] (50) (S)-1-(((R)-2-hydroxydodecyl)((1-(2-hydroxyethyl)-1H-pyrazole-4-yl)methyl)amino)dodecane-2-ol;

[0067] (51) di(pentadecan-7-yl)3,3'-(((1-(2-(bis(3-oxo-3-(pentadecan-7-yloxy)propyl)amino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)dipropionate;

[0068] (52) ((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl)) tetrakis(propaneoil))tetrakis(oxy))tetrakis(butane-4,1-diyl)tetranonanoate;

[0069] (53) tetrakis(2-ethylhexyl) 3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrapropionate;

[0070] (54) tetrakis(4-(2-cyclohexylacetoxy)butyl) 3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrapropionate;

[0071] (55) ((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy)) tetrakis(butane-4,1-diyl)tetraheptanoate;

[0072] (56) ((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl)) tetrakis(propaneoil))tetrakis(oxy))tetrakis(ethane-2,1-diyl)tetraheptanoate;

[0073] (57) ((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl)) tetrakis(propaneoil))tetrakis(oxy))tetrakis(butane-4,1-diyl)tetratridecanoate;

[0074] (58) Tetrakis(2-ethylhexyl) 4,4',4'',4''-((3,3',3'',3''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrabutyrate;

[0075] (59) Tetrakis(2-ethylhexyl) 6,6',6'',6''-((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrahexanoate;

[0076] (60) Tetrakis(2-propylhexyl) 4,4',4'',4''-((3,3',3'',3''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrabutyrate;

[0077] (61) Tetrakis(2-ethylpentyl) 4,4',4'',4'''-((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrabutyrate;

[0078] (62) Tetrakis(2-ethylpentyl) 6,6',6'',6'''-((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrahexanoate;

[0079] (63) tetra((Z)-non-2-en-1-yl) 9,9',9'',9'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryyl))tetranonanoate;

[0080] (64) (((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrakis(methylene))tetrakis(propane-2,1,3-triyl)octahexanoate;

[0081] (65) di(henicosan-10-yl) 3,3'-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(methylazandyl))dipropionate;

[0082] (66) ((3,3'-((3-(5-(3-hydroxypropyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)propyl)azandyl)bis(propaneoil))bis(oxy))bis(hexane-6,1-diyl)bis(2-hexyldecanoate.

[0083] In one embodiment of the present invention, the ionized lipid is heptadecan-9-yl 8-[2-hydroxyethyl-(6-oxo-6-undecooxyhexyl)amino]octanoate, (6Z,9Z,28Z,31Z)-hephtatriaconta-6,9,28,31-tetraene-19-yl4-(dimethylamino)butanoate, di(pentadecan-7-yl)3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandil)dipropionate, di(pentadecan-7-yl)6,6'-(((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)azandil)dihexanoate, tetrakis(2-ethylhexyl) 3,3',3'',3'''-(((2,5-Diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrapropionate, tetrakis(2-ethylpentyl) 4,4',4'',4'''-((3,3',3'',3'''-(((2,5-Diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrabutyrate, di(tridecan-6-yl) 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)dipropionate, Di(heptadecan-8-yl) 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)dipropionate, di(nonadecan-9-yl) 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)dipropionate, di(pentadecan-7-yl) 3,3'-(((1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)dipropionate, (((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)bis(ethane-2,1-diyl)bis(2-hexyldecanoate) and combinations thereof Can be selected in the military.

[0084] In one embodiment of the present invention, the selective organ target lipid may be represented by the following chemical formula 1:

[0085] [Chemical Formula 1]

[0086]

[0087] In the above chemical formula 1, R1 and R2 are each independently a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C2 to C30 alkenyl group, or a substituted or unsubstituted C2 to C30 alkynyl group, and

[0088] X and Y are each independently -COO-, -OCO-, -NHCO-, -CONH-, -CHOH-, a substituted or unsubstituted C1 to C5 alkylene group, a substituted or unsubstituted C2 to C5 alkenylene group or a substituted or unsubstituted C2 to C5 alkynylene group, and

[0089] Z is -O-, -N + R4R5-, -COO-, -OCO-, -NHCO-, -CONH-, single bond, substituted or unsubstituted C1 to C5 alkylene group, substituted or unsubstituted C2 to C5 alkenylene group or substituted or unsubstituted C2 to C5 alkynylene group, and R4 and R5 are each independently hydrogen or a substituted or unsubstituted C1 to C5 alkyl group, and

[0090] R3 is -COOH, -OH, -C5H 10 N + O2 - or -C7H4O2 - And,

[0091] m, n, o, and p are each independently integers from 0 to 10. In one embodiment of the present invention, the selective long-term target lipid may be selected from the group consisting of ceramide (C18:1 Ceramide(d18:1 / 18:1), N-oleoyl-D-erythro-sphingosine), DGTS (1,2-dipalmitoyl-sn-glycero-3-O-4'-(N,N,N-trimethyl)-homoserine), DOBAQ (N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propane-1-aminium), DHSG (1,5-dihexadecyl N-(3-carboxy-1-oxopropyl)-L-glutamate), 16:0 DGS (1,2-dipalmitoyl-sn-glycero-3-succinate) and combinations thereof.

[0092] In one embodiment of the present invention, the selective organ target lipid may not include a phosphate group.

[0093] In one embodiment of the present invention, the PEG lipid may be selected from the group consisting of DMG-PEG2000 (1,2-dimyristoyl-lac-glycero-3-methoxypolyethylene glycol-2000), DSPE-PEG2000 (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000]), ceramide-PEG2000 (N-palmitoyl-sphingosine-1-{succinyl[methoxy(polyethylene glycol)2000]}) and combinations thereof.

[0094] In one embodiment of the present invention, the helper lipid may be a phospholipid.

[0095] In one embodiment of the present invention, the composition may have a particle size (Z-average) of 50 nm to 300 nm.

[0096] In one embodiment of the present invention, the composition may comprise 10 mol% to 60 mol% of ionized lipids based on the sum of mol% of ionized lipids, selective organ target lipids, cholesterol, and PEG lipids; 5 mol% to 45 mol% of selective organ target lipids; 20 mol% to 65 mol% of cholesterol; and 0.9 mol% to 5 mol% of PEG lipids.

[0097] In one embodiment of the present invention, the composition may include 3 mol% to 20 mol% of helper lipids based on the sum of mol% of ionized lipids, selective organ target lipids, cholesterol, PEG lipids, and helper lipids.

[0098] In one embodiment of the present invention, the above-described composition may further include nucleic acid.

[0099] In one embodiment of the present invention, the nucleic acid may be selected from the group consisting of mRNA, siRNA, aiRNA, miRNA, dsRNA, shRNA, lncRNA, saRNA, rRNA, RNA, DNA, cDNA, plasmid, aptamer, tRNA, piRNA, circRNA, antisense oligonucleotide, ribozyme, PNA, DNAzyme, and combinations thereof.

[0100] In one embodiment of the present invention, the composition can be targeted and delivered to extrahepatic tissue.

[0101] In one embodiment of the present invention, the composition may be targeted and delivered to a spleen or immune cell.

[0102] The composition according to the present invention is effective for delivering drugs to specific tissues, particularly the spleen or immune cells, because it can maintain the administered dose at the target site by reducing the amount of drug lost. In addition, it exhibits excellent efficiency in delivering therapeutic molecules to cells and in vivo stability, which can contribute to improving the in vivo stability and therapeutic efficacy of nucleic acid therapeutics.

[0103] Figure 1 is a diagram showing the z-average diameter and polydispersity index (PDI) of a composition having the composition of Table 2, which is an embodiment of the present invention.

[0104] Figure 2 is a diagram illustrating the encapsulation efficiency of a composition having the composition of Table 2, which is an embodiment of the present invention.

[0105] FIG. 3 is a figure showing the expression rate of luminescent firefly luciferase protein in the spleen in relation to Comparative Example 1 and Examples 1 to 31.

[0106] FIG. 4 is a figure illustrating the expression efficiency of luminescent firefly luciferase proteins in the lungs, liver, and spleen in relation to Comparative Examples 2 to 7 and Examples 1 to 5, 9 to 13, 17 to 21 and 23 to 31.

[0107] FIG. 5 is a figure illustrating the presence or absence of luminescent firefly luciferase protein expression in the lungs, liver, and spleen in relation to Comparative Examples 2 to 7 and Examples 1 to 5, 9 to 13, 17 to 21 and 23 to 31.

[0108] Figures 6a to 6h illustrate the expression efficiency of lung immune cells according to intratracheal administration of each experimental example, indicated on the x-axis of each graph.

[0109] Embodiments of the present invention will be described in detail below. Prior to this, terms and words used in this specification and claims should not be interpreted as being limited to their ordinary or dictionary meanings. Instead, based on the principle that the inventor can appropriately define the concepts of terms to best describe their invention, they should be interpreted in a meaning and concept consistent with the technical spirit of the present invention. Therefore, the configurations described in the embodiments of this specification are merely one preferred embodiment of the present invention and do not represent all aspects of the technical spirit of the present invention. It should be understood that various equivalents and modifications capable of replacing them may exist at the time of filing this application.

[0110] Throughout this specification, when a part is described as 'comprising' a certain component, it means that, unless specifically stated otherwise, it does not exclude other components but may include additional components.

[0111] Furthermore, descriptions that specify components by limiting or adding them may be applied to all inventions unless there are special limitations, and are not limited to specific inventions.

[0112] In addition, throughout the description of the invention and claims of this application, items indicated in the singular include cases where they are plural unless otherwise noted.

[0113] In addition, throughout the description of the invention and the claims of the present invention, "or" includes "and" unless otherwise noted. Therefore, "comprising A or B" means all three of the above cases: including A, including B, or including both A and B.

[0114] In addition, all numerical ranges include the values ​​at both ends and all intermediate values ​​in between, unless explicitly stated to be excluded.

[0115] In this specification, the term "lipid nanoparticle (LNP)" refers to a structure in which a homogeneous phase is prepared by mixing lipids with a drug (e.g., a nucleic acid-based drug) at room temperature and dispersing it in an aqueous solution, so that the drug exists as a solid solution between lipid crystals. Since the lipid nanoparticles utilize substances present in the body such as phospholipids, lipids, and cholesterol, they have high bioavailability and affinity, enable drug release and control, and are particulate drug delivery systems with high stability against degradation by enzymes. Additionally, the lipid nanoparticles can encapsulate RNA by being positively charged at acidic pH, and can minimize toxicity by being neutrally charged at physiological pH.

[0116]

[0117] In one aspect of the present invention, the composition of the present invention provides a composition comprising an ionizable lipid, a selective organ targeting lipid, cholesterol, and a polyethylene glycol lipid. In another aspect of the present invention, the composition may further comprise a helper lipid.

[0118] Ionized lipids are generally composed of an ionizable head, a linker, and a terminal consisting of a hydrocarbon chain. They are known to play a key role in determining nucleic acid delivery efficiency by electrostatically binding to nucleic acids to encapsulate them and enabling the escape of nucleic acids from endosomes within the cell. Additionally, cholesterol maintains lipid nanoparticles in a rigid and stable manner, while PEG lipids prevent aggregation between lipid nanoparticles and ensure structural stability. Furthermore, helper lipids (e.g., phospholipids) play a role in maintaining the lipid bilayer structure of lipid nanoparticles.

[0119] Selective organ-targeted lipids are a critical component in the design of lipid nanoparticles that can enhance therapeutic efficacy and reduce side effects by selectively targeting specific organs or tissues to deliver therapeutic agents. Selective organ-targeted lipids are often chemically modified to contain target portions, such as ligands or antibodies, that can specifically bind to receptors or other markers unique to specific cells or tissues; this specificity ensures that lipid nanoparticles accumulate preferentially in target organs. In addition to their targeting function, these lipids help form a stable bilayer structure for the lipid nanoparticles. They can be customized to adjust nanoparticle size, charge, and stability, which are critical factors for circulation time and bioavailability. Furthermore, the design of selective organ-targeted lipid nanoparticles can influence how they interact with cell membranes, facilitating the fusion or endocytosis necessary for cell entry, and can aid in the release of therapeutic payloads from the lipid nanoparticles into the cytoplasm once inside the target cell.

[0120] In one embodiment of the present invention, the ionized lipid may be a lipid comprising 1 to 10 nitrogen atoms and 1 to 10 biodegradable bonds. The biodegradable bonds refer to chemical bonds that can be hydrolyzed or degraded by enzymes, water, or under specific pH conditions in vivo, and specifically may be ester bonds, amide bonds, or disulfide bonds, but are not necessarily limited thereto.

[0121] In one embodiment of the present invention, the ionized lipid may be a lipid comprising 1 to 8 nitrogen atoms and 1 to 9 biodegradable bonds, or a lipid comprising 1 to 5 nitrogen atoms and 1 to 8 biodegradable bonds. In one embodiment of the present invention, the biodegradable bond may be an ester bond.

[0122] In one embodiment of the present invention, the ionized lipid comprises a pyrazole structure or a diazabicyclo structure and may comprise one to ten ester bonds. The pyrazole structure refers to an aromatic heterocycle comprising two nitrogen atoms not adjacent to the 1,2-position within the ring. Additionally, the diazabicyclo structure refers to a bicyclic structure comprising two nitrogen atoms. The number of ester bonds may be one to ten, one to nine, or one to eight.

[0123] In one embodiment of the present invention, the ionized lipid may be one or more compounds selected from the group consisting of the following. Additionally, the ionized lipid may refer to the compounds described in Korean Patent Applications No. 10-2023-0143205 and No. 10-2023-0143867:

[0124] (1) bis(2-propylhexyl)6,6'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))dihexanoate;

[0125] (2) bis(2-propylhexyl)8,8'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))dioctanoate;

[0126] (3) bis(2-ethylpentyl)4,4'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))dibutyrate;

[0127] (4) bis(2-ethylpentyl)6,6'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))dihexanoate;

[0128] (5) bis(2-ethylpentyl)8,8'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))dioctanoate;

[0129] (6) (((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(methylene))bis(propane-2,1,3-triyl)tetrahexanoate;

[0130] (7) (((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(methylene))bis(propane-2,1,3-triyl)tetraoctanoate;

[0131] (8) (((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(methylene))bis(propane-2,1,3-triyl) tetrakis(decanoate);

[0132] (9) di(henicosan-10-yl)3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)methyl)azandyl)dipropionate;

[0133] (10) di(pentadecan-7-yl)3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)dipropionate;

[0134] (11) 1,1'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(tetradecane-2-ol);

[0135] (12) (((1-(2-(bis(6-((2-hexyldecanoyl)oxy)hexyl)amino)ethyl)-1H-pyrazole-4-yl)methyl)azandil)bis(hexane-6,1-diyl)bis(2-hexyldecanoate);

[0136] (13) di((Z)-non-2-en-1-yl)9,9'-(((1-(2-(bis(9-(((Z)-non-2-en-1-yl)oxy)-9-oxononyl)amino)ethyl)-1H-pyrazol-4-)methyl)azandyl)dinonanoate;

[0137] (14) N-((1-(2-(ditetradecylamino)ethyl)-1H-pyrazole-4-yl)methyl)-N-tradecyltetradecane-1-amine;

[0138] (15) (((((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(ethane-2,1-diyl))bis(azantryl))tetrakis(hexane-6,1-diyl)tetrakis(2-hexyldecanoate);

[0139] (16) (((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)azandil)bis(hexane-6,1-diyl)bis(2-hexyldecanoate);

[0140] (17) di(pentadecan-7-yl)6,6'-(((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)azandyl)dihexanoate;

[0141] (18) (((((1-(2-hydroxyethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(ethane-2,1-diyl))bis(azantryl))tetrakis(hexane-6,1-diyl)tetrakis(2-hexyldecanoate);

[0142] (19) (((((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(ethane-2,1-diyl))bis(azantryl))tetrakis(hexane-6,1-diyl)tetrakis(2-hexyldecanoate);

[0143] (20) di((Z)-non-2-en-1-yl)9,9'-(((1-(2-(bis(2-hydroxyethyl)amino)ethyl)-1H-pyrazol-4-yl)methyl)azandyl)dinonanoate;

[0144] (21) didodecyl 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)dipropionate;

[0145] (22) Didodecyl 3,3'-(((1-(2-hydroxyethyl)-1H-pyrazole-4-yl)methyl)azandyl)dipropionate;

[0146] (23) didodecyl 3,3'-(((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)azandiyl)dipropionate;

[0147] (24) 11-((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)-24-hexyl-8,14,23-trioxo-7,15,22-trioxa-11-azadotriacontyl 2-hexyl undecanoate;

[0148] (25) 24-hexyl-11-((1-(2-hydroxyethyl)-1H-pyrazole-4-yl)methyl)-8,14,23-trioxo-7,15,22-trioxa-11-azadotriacontyl 2-hexyl undecanoate;

[0149] (26) 24-hexyl-11-((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)-8,14,23-trioxo-7,15,22-trioxa-11-azadotriacontyl 2-hexyl undecanoate;

[0150] (27) Dioctyl 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)methyl)azandyl)dipropionate;

[0151] (28) Dihexadecyl 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)dipropionate;

[0152] (29) ((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(butane-4,1-diyl)bis(2-hexyldecanoate);

[0153] (30) di((Z)-non-2-en-1-yl) 9,9'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)dinonanoate;

[0154] (31) di((Z)-non-2-en-1-yl) 9,9'-(((1-(2-hydroxyethyl)-1H-pyrazole-4-yl)methyl)azandyl)dinonanoate;

[0155] (32) di((Z)-non-2-en-1-yl) 9,9'-(((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)azandyl)dinonanoate;

[0156] (33) bis(4-(propionyloxy)butyl) 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl) dipropionate;

[0157] (34) ((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(butane-4,1-diyl)dipentanoate;

[0158] (35) ((3,3'-(((1-(2-(dimethylamino)ethyl)- 1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(butane-4,1-diyl) diheptanoate;

[0159] (36) ((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(butane-4,1-diyl)dinonanoate;

[0160] (37) ((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(butane-4,1-diyl) diundecanoate;

[0161] (38) ((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(ethane-2,1-diyl) diheptanoate;

[0162] (39) ((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(propane-3,1-diyl)dihexanoate;

[0163] (40) ((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandil)bis(propanoyl))bis(oxy))bis(pentane-5,1-diyl)dibutyrate;

[0164] (41) bis(2-ethylhexyl)4,4'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandil)bis(propanoyl))bis(oxy))dibutyrate;

[0165] (42) bis(2-ethylhexyl)6,6'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandil)bis(propanoyl))bis(oxy))dihexanoate;

[0166] (43) bis(2-ethylhexyl)8,8'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandil)bis(propanoyl))bis(oxy))dioctanoate;

[0167] (44) bis(2-propylhexyl)4,4'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))dibutyrate;

[0168] (45) (2R,2'R)-1,1'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandiyl)bis(decan-2-ol);

[0169] (46) (S)-1-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)((R)-2-hydroxydecyl)amino)decane-2-ol;

[0170] (47) (2R,2'R)-1,1'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandiyl)bis(dodecane-2-ol);

[0171] (48) (S)-1-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)((R)-2-hydroxydodecyl)amino)dodecane-2-ol;

[0172] (49) (2R,2'R)-1,1'-(((1-(2-hydroxyethyl)-1H-pyrazole-4-yl)methyl)azandiyl)bis(dodecane-2-ol);

[0173] (50) (S)-1-(((R)-2-hydroxydodecyl)((1-(2-hydroxyethyl)-1H-pyrazole-4-yl)methyl)amino)dodecane-2-ol;

[0174] (51) di(pentadecan-7-yl)3,3'-(((1-(2-(bis(3-oxo-3-(pentadecan-7-yloxy)propyl)amino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)dipropionate;

[0175] (52)((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl)) tetrakis(propaneoil))tetrakis(oxy))tetrakis(butane-4,1-diyl)tetranonanoate;

[0176] (53) tetrakis(2-ethylhexyl) 3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrapropionate;

[0177] (54) tetrakis(4-(2-cyclohexylacetoxy)butyl) 3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrapropionate;

[0178] (55) ((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy)) tetrakis(butane-4,1-diyl)tetraheptanoate;

[0179] (56) ((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl)) tetrakis(propaneoil))tetrakis(oxy))tetrakis(ethane-2,1-diyl)tetraheptanoate;

[0180] (57) ((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl)) tetrakis(propaneoil))tetrakis(oxy))tetrakis(butane-4,1-diyl)tetratridecanoate;

[0181] (58) Tetrakis(2-ethylhexyl) 4,4',4'',4''-((3,3',3'',3''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrabutyrate;

[0182] (59) Tetrakis(2-ethylhexyl) 6,6',6'',6''-((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrahexanoate;

[0183] (60) Tetrakis(2-propylhexyl) 4,4',4'',4''-((3,3',3'',3''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrabutyrate;

[0184] (61) Tetrakis(2-ethylpentyl) 4,4',4'',4'''-((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrabutyrate;

[0185] (62) Tetrakis(2-ethylpentyl) 6,6',6'',6'''-((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrahexanoate;

[0186] (63) tetra((Z)-non-2-en-1-yl) 9,9',9'',9'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryyl))tetranonanoate;

[0187] (64) (((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrakis(methylene))tetrakis(propane-2,1,3-triyl)octahexanoate;

[0188] (65) di(henicosan-10-yl) 3,3'-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(methylazandyl))dipropionate;

[0189] (66) ((3,3'-((3-(5-(3-hydroxypropyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)propyl)azandyl)bis(propaneoil))bis(oxy))bis(hexane-6,1-diyl)bis(2-hexyldecanoate.

[0190] In one embodiment of the present invention, the ionized lipid may be selected from the group consisting of heptadecan-9-yl 8-[2-hydroxyethyl-(6-oxo-6-undecooxyhexyl)amino]octanoate, (6Z,9Z,28Z,31Z)-hephtatriaconta-6,9,28,31-tetraene-19-yl 4-(dimethylamino)butanoate and combinations thereof.

[0191] In one embodiment of the present invention, the ionized lipid is heptadecan-9-yl 8-[2-hydroxyethyl-(6-oxo-6-undecooxyhexyl)amino]octanoate, (6Z,9Z,28Z,31Z)-hephtatriaconta-6,9,28,31-tetraene-19-yl4-(dimethylamino)butanoate, di(pentadecan-7-yl)3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandil)dipropionate, di(pentadecan-7-yl)6,6'-(((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)azandil)dihexanoate, tetrakis(2-ethylhexyl) 3,3',3'',3'''-(((2,5-Diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrapropionate, tetrakis(2-ethylpentyl) 4,4',4'',4'''-((3,3',3'',3'''-(((2,5-Diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrabutyrate, di(tridecan-6-yl) 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)dipropionate, Di(heptadecan-8-yl) 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)dipropionate, di(nonadecan-9-yl) 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)dipropionate, di(pentadecan-7-yl) 3,3'-(((1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)dipropionate, (((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)bis(ethane-2,1-diyl)bis(2-hexyldecanoate) and combinations thereof It can be selected from the group. The structures of the above ionized lipids are listed in Table 1 below.

[0192] Compound structural formula SM-102 heptadecan-9-yl 8-[2-hydroxyethyl-(6-oxo-6-undecooxyhexyl)amino]octanoate MC3(6Z,9Z,28Z,31Z)-hephtatriaconta-6,9,28,31-tetraene-19-yl4-(dimethylamino)butanoate Lipid 1-di(pentadecan-7-yl)6,6'-(((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)azandyl)dihexanoate Lipid 2-di(pentadecan-7-yl)3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)dipropionate Lipid 3-tetrakis(2-ethylhexyl) 3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrapropionate Lipid 4-tetrakis(2-ethylpentyl) 4,4',4'',4''-((3,3',3'',3''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrabutyrate Lipid 5-di(tridecan-6-yl) 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)dipropionate Lipid 6-di(heptadecan-8-yl) 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)dipropionate Lipid 7-di(nonadecan-9-yl) 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)dipropionate Lipid 8-di(pentadecan-7-yl) 3,3'-(((1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)dipropionate Lipid 9(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)bis(ethane-2,1-diyl)bis(2-hexyldecanoate)

[0193]

[0194] In one embodiment of the present invention, the ionized lipid may have an asymmetric center, a chiral axis, and a chiral plane, and may appear as a racemic mixture, a racemic mixture, and individual diastereomers, wherein all possible isomers, including optical isomers, and mixtures thereof are included in the ionized lipid of the present invention.

[0195]

[0196] In one embodiment of the present invention, the selective organ target lipid may be a compound represented by the following chemical formula 1.

[0197] [Chemical Formula 1]

[0198]

[0199] In the above chemical formula 1, R1 and R2 are each independently a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C2 to C30 alkenyl group, or a substituted or unsubstituted C2 to C30 alkynyl group, and

[0200] X and Y are each independently -COO-, -OCO-, -NHCO-, -CONH-, -CHOH-, a substituted or unsubstituted C1 to C5 alkylene group, a substituted or unsubstituted C2 to C5 alkenylene group or a substituted or unsubstituted C2 to C5 alkynylene group, and

[0201] Z is -O-, -N + R4R5-, -COO-, -OCO-, -NHCO-, -CONH-, single bond, substituted or unsubstituted C1 to C5 alkylene group, substituted or unsubstituted C2 to C5 alkenylene group or substituted or unsubstituted C2 to C5 alkynylene group, and R4 and R5 are each independently hydrogen or a substituted or unsubstituted C1 to C5 alkyl group, and

[0202] R3 is -COOH, -OH, -C5H 10 N + O2 - or -C7H4O2 - And,

[0203] m, n, o, and p are each independently integers from 0 to 10.

[0204] The above -COO-, -OCO-, -NHCO-, -CONH-, -CHOH-, -C5H 10 N + O2 - , -C7H4O2 - , -N + R4R5- are respectively, , , , , , , , It means a structure like that.

[0205] In one embodiment of the present invention, R1 to R2 may each independently be a substituted or unsubstituted C5 to C25 alkyl group, a substituted or unsubstituted C5 to C25 alkenyl group, or a substituted or unsubstituted C5 to C25 alkynyl group, and R1 to R2 may each independently be a substituted or unsubstituted C10 to C20 alkyl group, a substituted or unsubstituted C10 to C20 alkenyl group, or a substituted or unsubstituted C10 to C20 alkynyl group.

[0206] In one embodiment of the present invention, X and Y are each independently -COO-, -OCO-, -NHCO-, -CONH-, -CHOH-, an unsubstituted C1 to C5 alkylene group or an unsubstituted C2 to C5 alkenylene group, and Z is -O-, -N + R4R5-, -COO-, -OCO-, -NHCO-, -CONH- or a single bond, where R4 and R5 are both unsubstituted C1 alkyl groups, and R3 is -COOH, -OH, -C5H 10 N + O2 - or -C7H4O2 -And, m, n, o and p can each independently be 0 to 10, 0 to 8, or 0 to 5.

[0207] In one embodiment of the present invention, the selective long-term target lipid is a ceramide represented by Formula 1-1 (C18:1 Ceramide(d18:1 / 18:1), N-oleoyl-D-erythro-sphingosine), DGTS represented by Formula 1-2 (1,2-dipalmitoyl-sn-glycero-3-O-4'-(N,N,N-trimethyl)-homoserine), DOBAQ represented by Formula 1-3 (N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propane-1-amulium), DHSG represented by Formula 1-4 (1,5-dihexadecyl N-(3-carboxy-1-oxopropyl)-L-glutamate), 16:0 DGS represented by Formula 1-5 (1,2-dipalmitoyl-sn-glycero-3-succinate), and combinations thereof. It can be selected from the formed group.

[0208] [Chemical Formula 1-1]

[0209]

[0210] [Chemical Formula 1-2]

[0211]

[0212] [Chemical Formula 1-3]

[0213]

[0214] [Chemical Formula 1-4]

[0215]

[0216] [Chemical Formula 1-5]

[0217]

[0218] In one embodiment of the present invention, the selective organ target lipid may not contain a phosphate group. Conventionally, negatively charged phospholipids have been used as selective organ target lipids for spleen delivery, but the selective organ target lipid used in the present invention does not contain a phosphate group and is characterized by having a carboxyl group, being amphoteric, or having a positive or negative charge.

[0219] In the composition according to the present invention, the cholesterol may be the cholesterol commonly used to manufacture lipid nanoparticles.

[0220] In the composition according to the present invention, the PEG lipid (Polyethylene glycol Lipid) may be selected from the group consisting of PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, and PEG-modified dialkylglycerol, but is not limited thereto. The term “modification” means introducing a new functional group into the structure of a specific compound. For example, “PEG-modified phosphatidylethanolamine” refers to a compound in which a PEG chain is bonded to a phosphatidylethanolamine structure.

[0221] Additionally, the PEG lipid may include a PEG portion having a size of 100 Da to 20 kDa, and specifically may be selected from the group consisting of DMG-PEG2000 (1,2-dimyristoyl-lac-glycero-3-methoxypolyethyleneglycol-2000), DSPE-PEG2000 (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethyleneglycol)-2000]), ceramide-PEG2000 (N-palmitoyl-sphingosine-1-{succinyl[methoxy(polyethyleneglycol)2000]}) and combinations thereof, but is not limited thereto.

[0222] In another aspect of the present invention, the PEG-lipid may comprise a linker moiety suitable for binding PEG to lipid nanoparticles. The linker moiety may be selected from, but is not limited to, the group consisting of carbonate (-OC(O)O-), succinoyl, phosphate ester (-O-(O)POH-O-), sulfonate ester, amido (-C(O)NH-), amino (-NR-), carbonyl (-C(O)-), carbamate (-NHC(O)O-), urea (-NHC(O)NH-), disulfide (-SS-), ether (-O-), succinyl (-(O)CCH2CH2C(O)-), succinamidyl (-NHC(O)CH2CH2C(O)NH-) and combinations thereof.

[0223] In one aspect of the present invention, the helper lipid and / or cholesterol described below of the composition may be used as the lipid constituting the PEG-lipid, but any lipid capable of binding with PEG may be used without limitation.

[0224] In the composition according to the present invention, the helper lipid may be a phospholipid. The above helper lipids are specifically DMPC (1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine), DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), DOPI (1,2-dioleoyl-sn-glycero-3-phospho-(1'-myo-inositol)), DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), DSPI (1,2-distearoyl-sn-glycero-3-phosphoinositol), and DLPC (1,2-dilinoreyl-sn-glycero-3-phosphocholine), 1,2-Dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-Diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-D-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 diether PC), 1-oleoyl-2-cholesteryl-hemiscu-sinoyl-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-Dipitanoyl-sn-glycero-3-phosphoethanolamine (4ME 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-phosphoethanolamine, 1,2-Dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), Dipalmitoyl phosphatidylglycerol (DPPG), palmitoyl oleoyl phosphatidyl ethanolamine (POPE), distearoyl-phosphatidyl-ethanolamine (DSPE),It may be one or more selected from the group consisting of dipalmitoyl phosphatidylethanolamine (DPPE), dimyristoyl phosphoethanolamine (DMPE), 1-stearoyl-2-oleoyl-phosphatidylethanolamine (SOPE), 1-stearoyl-2-oleoyl-phosphatidylcholine (SOPC), sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, palmitoyl oleoyl phosphatidylcholine, lysophosphatidylcholine, and lysophosphatidyl ethanolamine (LPE), but is not limited thereto.

[0225] In addition, in the composition according to the present invention, the helper lipid may be a glycerophospholipid. The glycerophospholipid refers to a phospholipid having a glycerol backbone. The above helper lipids may be one or more selected from the group consisting of DMPC (1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine), DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), DOPI (1,2-dioleoyl-sn-glycero-3-phospho-(1'-myo-inositol)), DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), DSPI (1,2-distearoyl-sn-glycero-3-phosphoinositol), and DLPC (1,2-dilinoreyl-sn-glycero-3-phosphocholine), but It is not limited.

[0226] In one aspect of the present invention, the composition according to the present invention may have a particle size (Z-average) of 50 nm to 300 nm. The particle size of the composition may be measured using a Zetasizer Pro (Malvern Instruments, United Kingdom), and the particle size may be measured after dilution using 1X DPBS.

[0227] In one aspect of the present invention, a composition according to the present invention may comprise 10 mol% to 60 mol% of ionized lipids based on the sum of mol% of ionized lipids, selective organ target lipids, cholesterol, and PEG lipids; 5 mol% to 45 mol% of selective organ target lipids; 20 mol% to 65 mol% of cholesterol; and 0.9 mol% to 5 mol% of PEG lipids. In another aspect of the present invention, a composition of the present invention may comprise 15 mol% to 50 mol%, 20 mol% to 40 mol%, or 25 mol% to 35 mol% of ionized lipids based on the sum of mol% of ionized lipids, selective organ target lipids, cholesterol, and PEG lipids. In another aspect of the present invention, the composition of the present invention may comprise 8 mol% to 40 mol%, 10 mol% to 38 mol%, or 15 mol% to 35 mol% of selective organ target lipids based on the sum of mol% of ionized lipids, selective organ target lipids, cholesterol, and PEG lipids. In another aspect of the present invention, the composition of the present invention may comprise 25 mol% to 63 mol%, 30 mol% to 60 mol%, or 33 mol% to 58 mol% of cholesterol based on the sum of mol% of ionized lipids, selective organ target lipids, cholesterol, and PEG lipids. In another aspect of the present invention, the composition of the present invention may comprise 1 mol% to 4.5 mol%, 1.5 mol% to 4.0 mol%, or 2.0 mol% to 3.5 mol% of PEG lipids based on the sum of mol% of ionized lipids, selective organ target lipids, cholesterol, and PEG lipids.

[0228] In one aspect of the present invention, the composition according to the present invention may further comprise 3 mol% to 20 mol% of helper lipids based on the sum of mol% of ionized lipids, selective organ target lipids, cholesterol, PEG lipids, and helper lipids. In another aspect of the present invention, the composition of the present invention may further comprise 4 mol% to 15 mol%, 5 mol% to 10 mol%, or 6 mol% to 9 mol% of helper lipids based on the sum of mol% of ionized lipids, selective organ target lipids, cholesterol, PEG lipids, and helper lipids.

[0229] In one aspect of the present invention, the composition according to the present invention may further include an ionic drug.

[0230] In another aspect of the present invention, the ionic drug may be one or more selected from the group consisting of nucleic acids or nucleic acid-based drugs, peptides, protein drugs, protein-nucleic acid structures, and ionic biopolymer-drug conjugates.

[0231] In one embodiment of the present invention, the nucleic acid may be selected from the group consisting of mRNA, siRNA, aiRNA, miRNA, dsRNA, shRNA, lncRNA, saRNA, rRNA, RNA, DNA, cDNA, plasmid, aptamer, tRNA, piRNA, circRNA, antisense oligonucleotide, ribozyme, PNA, DNAzyme, and combinations thereof, and most preferably may be mRNA, but is not limited thereto.

[0232] In another embodiment of the present invention, the ionic drug may be a therapeutic agent for treating a disease or a preventive agent for preventing it.

[0233] In another aspect of the present invention, the composition may be used as a pharmaceutical composition for treating diseases.

[0234] In one aspect of the present invention, the composition may include ordinary non-toxic and pharmaceutically acceptable additives. Additives that may be used in the composition of the present invention include sweeteners, binders, solubilizers, solubilizing aids, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, etc. Examples include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterine, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth gum, arginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla scent, etc.

[0235] The composition of the present invention can be prepared in various forms of oral administration, such as tablets, pills, powders, capsules, syrups, or emulsions, or in forms of parenteral administration, such as intramuscular, intravenous, or subcutaneous administration.

[0236] When the composition of the present invention is formulated in the form of oral administration, cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspending agent, emulsifier, diluent, etc. may be used as additives.

[0237] In addition, when the composition of the present invention is formulated in the form of an injection, water, saline solution, glucose aqueous solution, similar sugar aqueous solution, alcohol, glycol, ether, oil, fatty acid, fatty acid ester, glyceride, surfactant, suspending agent, emulsifier, etc. may be used as additives.

[0238] The composition of the present invention can be targeted and delivered to extrahepatic tissues, specifically the spleen or immune cells (immune cells, macrophages, DC cells, T cells, neutrophils, eosinophils, NK cells, etc.) by including the selective organ target lipids.

[0239] Specific embodiments of the present invention are presented below. However, the embodiments described below are merely for the purpose of specifically illustrating or explaining the present invention and do not limit the present invention. Furthermore, details not described herein can be sufficiently technically inferred by a person skilled in the art, so their description is omitted.

[0240] Experimental Example 1. Characteristics of a composition containing selective long-term target lipids (SORT lipids)

[0241] [Preparation of composition]

[0242] Cholesterol purchased from Sigma Aldrich (USA) was used for the preparation of the composition, and DMG-PEG2000 (1,2-Dimyristoyl-racglycero-3-methoxypolyethylene glycol-2000) purchased from Avanti Polar Lipids (USA) was used as the PEG lipid. DSPC (1,2-Distearoyl-sn-glycero-3-PC) or DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) purchased from Avanti Polar Lipids (USA) was used as the helper lipid (phospholipid). Specifically, among the experimental examples using phospholipids, Comparative Examples 1, 2, 3 and Examples 1, 28, 29, 30, 31 used DSPC, while the others (Comparative Examples 4, 5, 6, 7 and Example 10) used DOPE. SM-102, MC3, Lipid 1 to Lipid 9 described below were used as ionizable lipids.

[0243] As selective organ targeting lipids (SORT lipids), ceramide, DGTS, DOBAQ, DHSG, and DGS were dissolved in ethanol along with ionized lipids, helper lipids (phospholipids), cholesterol, and PEG lipids, respectively, according to the compositions listed in Table 2 below.

[0244] The above ethanol solution and citrate buffer (pH 4.0, 50 mM) in which mRNA was dissolved were mixed in a 1:3 volume ratio. CleanCap Firefly Luciferase mRNA (N1m) was used.

[0245] NanoAssemblr Ignite for composition preparation TMA Precision Nanosystems, Inc. (Canada) was used, and a total flow rate (TFR) of 12 mL / min was adopted. Ethanol was removed from the prepared composition using an Amicon Ultra Centrifugal Filter, MWCO 10 kDa (Millipore, USA), the buffer was exchanged, and the composition was subsequently concentrated. For dilution, concentration, and exchange, 1X DPBS (Thermo Scientific, USA) was used.

[0246] No. Ionizable lipid SORT lipid Molar percentage (%) Ionizable lipid SORT lipidphospholipid Cholesterol DMG-PEG Comparative Example 1 SM-102BMP45109 (DSPC) 34.6 5 1.35 Comparative Example 2 SM-102-50-10 (DPSC) 38.5 1.5 Comparative Example 3 MC3-50-10 (DSPC) 38.5 1.5 Comparative Example 4 Lipid 1-50-10 (DOPE) 38.5 1.5 Comparative Example 5 Lipid 2-50-10 (DOPE) 38.5 1.5 Comparative Example 6 Lipid 3-35-10 (DOPE) 52.5 2.5 Comparative Example 7 Lipid 4-36.5-20 (DOPE) 51.52 Example 1 SM-102DHSG45109 (DSPC) 34.65 1.35 Example 2 SM-102 DOBAQ4510-43.65 1.35 Example 3 SM-102 Ceramide 3340-25.5 1.5 Example 4 SM-102 DGTS 38.530-30 1.5 Example 5 MC3 DHSG 4510-43.65 1.35 Example 6 MC3 DOBAQ4515-38.65 1.35 Example 7 MC3 Ceramide 3340-25.5 1.5 Example 8 MC3 DGTS 38.530-30 1.5 Example 9 Lipid 1 DHSG 4510-43.65 1.35 Example 10 Lipid 1 DOBAQ45159 (DOPE) 29.65 1.35 Example 11 Lipid 1 Ceramide 3340-25.51.5 Example 12 Lipid 1 DGTS 38.530-301.5 Example 13 Lipid 2 DHSG 4510-43.651.35 Example 14 Lipid 2 DOBAQ 4515-38.651.35 Example 15 Lipid 2 Ceramide 3340-25.51.5 Example 16 Lipid 2 DGTS 38.530-301.5 Example 17 Lipid 3 DHSG 3510-52.52.5 Example 18 Lipid 3 DOBAQ 3515-47.52.5 Example 19 Lipid 3 Ceramide 3540-22.52.5 Example 20 Lipid 3DGTS38.530-301.5 Example 21 Lipid 4DHSG26.510-61.52 Example 22 Lipid 4DOBAQ26.515-56.52 Example 23 Lipid 4 Ceramide26.540-31.52 Example 24 Lipid 4DGTS26.530-41.52 Example 25 Lipid 5DHSG455-48.51.5 Example 26 Lipid 6DHSG455-48.51.5 Example 27 Lipid 7DHSG455-48.51.5 Example 28 Lipid 8DHSG45510 (DSPC)33.51.5 Example 29 Lipid 9DHSG45510 (DSPC)33.51.5 Example 30 Lipid 1DHSG451010 (DSPC)33.51.5 Example 31 Lipid 1DGS451010 (DSPC)33.51.5.

[0247]

[0248] SM-102: Heptadecan-9-yl 8-[2-hydroxyethyl-(6-oxo-6-undecooxyhexyl)amino]octanoate

[0249] MC3: (6Z,9Z,28Z,31Z)-hephtatriaconta-6,9,28,31-tetraene-19-yl4-(dimethylamino)butanoate

[0250] Lipid 1: di(pentadecan-7-yl)6,6'-(((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)azandyl)dihexanoate

[0251] Lipid 2: di(pentadecan-7-yl)3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)dipropionate

[0252] Lipid 3: tetrakis(2-ethylhexyl) 3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrapropionate

[0253] Lipid 4: Tetrakis(2-ethylpentyl) 4,4',4'',4''-((3,3',3'',3''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrabutyrate

[0254] Lipid 5: di(tridecan-6-yl) 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)dipropionate

[0255] Lipid 6: di(heptadecan-8-yl) 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)dipropionate

[0256] Lipid 7: di(nonadecan-9-yl) 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)dipropionate

[0257] Lipid 8: di(pentadecan-7-yl) 3,3'-(((1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)dipropionate

[0258] Lipid 9: (((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)bis(ethane-2,1-diyl)bis(2-hexyldecanoate)

[0259] BMP: Bis(monoacylglycero)phosphate

[0260] DHSG: 1,5-Dihexadecyl N-(3-carboxy-1-oxopropyl)-L-glutamate

[0261] DOBAQ: N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyoxy)propane-1-amulium

[0262] Ceramide: C18:1 Ceramide (d18:1 / 18:1), N-oleoyl-D-erythro-sphingosine

[0263] DGTS: 1,2-Dipalmitoyl-sn-glycero-3-O-4'-(N,N,N-trimethyl)-homoserine

[0264] DGS: 16:0 DGS(1,2-dipalmitoyl-sn-glycero-3-succinate)

[0265] DMG-PEG: DMG-PEG2000 (1,2-dimyristoyl-lac-glycero-3-methoxypolyethylene glycol-2000)

[0266] [Method for Analyzing the Physicochemical Properties of the Composition]

[0267] The particle size, z-average diameter, and polydispersity index (PDI) were analyzed using Zetasizer Pro (Malvern Instruments, United Kingdom). Measurements were taken with a 1X DPBS dilution. The "PDI" is a ratio describing the homogeneity of the particle size distribution of the system; a PDI closer to 0 indicates monodispersity, while a PDI closer to 1 indicates polydispersity.

[0268] [MRNA Quantification and Encapsulation Efficiency (EE %) Measurement Method]

[0269] To measure mRNA content and encapsulation efficiency, a Ribogreen RNA assay kit (Invitrogen, USA) was used. Standard solutions ranging from 0 to 1000 ng / mL were prepared using ribosomal RNA, and samples were diluted to fall within this range. 50 μL of the sample or standard solution was loaded into 96-well microplates, followed by 50 μL of 1X TE buffer or 1% TritonX-100 solution. The plates were then incubated at room temperature for 10 minutes. After loading 100 μL of Ribogreen reagent solution diluted to a ratio of 1 / 200, fluorescence was measured using a microplate reader (Enspire 2300, PerkinElmer, USA) (Excitation 485 nm, Emission 530 nm).

[0270] The z-average diameter and PDI of the prepared composition are shown in Fig. 1, and the EE (%) is shown in Fig. 2.

[0271] The composition containing the present invention's selective organ-targeted lipids was found to have a z-average diameter of 300 nm or less and a narrow particle size distribution with a PDI of less than 0.2.

[0272]

[0273] Experimental Example 2. Expression efficiency in the spleen following intravenous administration of a composition containing selective organ-targeted lipids

[0274] To evaluate drug delivery distribution and in vivo transfection efficiency after systemic administration of the prepared substance, the composition of Experimental Example 1 was injected into Balb / c mice (male, 6 weeks old) via tail vein injection (administration volume 200 μL). 6 hours after injection, 150 mg / kg of D-Luciferin (Perkin Elmer, USA) was administered intraperitoneally, and 10 minutes later, luminescence in major organs (lungs, liver, spleen) was measured using IVIS Luminar XR (Perkin Elmer, USA).

[0275] In relation to Comparative Example 1 and Examples 1 to 31, the expression rate of luminescent firefly luciferase protein in the spleen is shown in FIG. 3, and in relation to Comparative Examples 2 to 7 and Examples 1 to 5, 9 to 13, 17 to 21, and 23 to 31, the expression efficiency and presence or absence of luminescent firefly luciferase protein in the lungs, liver, and spleen are shown in FIG. 4 and FIG. 5. In FIG. 5, photographs of each organ correspond to the lungs, liver, and spleen in order from left to right.

[0276] As confirmed in FIGS. 3 to 5, the composition of the present invention showed superior expression efficiency in the spleen compared to the comparative example that did not contain the selective organ target lipid of the present invention.

[0277]

[0278] Experimental Example 3. Expression efficiency in lung immune cells following intratracheal administration of a composition containing selective organ-targeted lipids

[0279] To evaluate drug delivery distribution and in vivo transfection efficiency following intratracheal administration of the prepared substance, the composition of Experimental Example 1 was injected into Balb / c mice (male, 6 weeks old) via intratracheal injection. Eight hours after administration, the mice were euthanized, and the lungs were perfused through the right ventricle to remove red blood cells and circulating leukocytes. The mouse lungs were then dissected into individual lobes, and washed in a Petri dish containing pH 7.2 PBS to remove any remaining blood. After removing the thymus, heart, blood vessels, bronchi, and connective tissues of the lung tissues, the dissected lung lobes were transferred to gentle MACS C tubes containing a prepared enzyme mixture. The enzyme mixture was prepared by adding 1× Buffer S, Enzyme D, and Enzyme A to the gentle MACS C tubes, and the enzyme solution was slowly injected into each lung lobe to induce dilation. Subsequently, the program was executed after attaching a gentle MACS Dissociator. After the program ended, Tube C was separated from the Dissociator, and the resuspended sample was filtered through a MACS Smart Strainer, centrifuged for 10 minutes, and the supernatant was removed. Subsequently, Debris Removal Solution was added to allow PBS to form a layer over the cell suspension, and the sample was centrifuged to completely remove the supernatant. Then, RBCs were removed using 1x RBC Lysis Buffer, followed by a wash with buffer. To confirm cell-specific expression, antibodies (Invitrogen, L34957), Anti-CD45-BV786 (BD, 564225), Anti-Ep-CAM (CD326)-BV605 (Biolegend, 118227), CD31-PE-Cy7 (ebioscience, 25-0311-82), Anti-Ly6G-PE (BD, 551461), and Anti-Siglec-F-PerCP-Cy5 were used.After staining with 5 (BD, 565526), ​​Anti-CD11b-APC-Cy7 (BD, 557657), Anti-MHCII-AF700 (Invitrogen, 56-5321-82), Anti-CD11c-V450 (BD, 560521), Anti-CD24-BV711 (BD, 563450), Anti-CD64-FITC (Biolegend, 139316), and Anti-F4 / 80-APC (Invitrogen, 17-4801-82), the cells were analyzed using a FACs instrument (BD FAC Symphony™ A5 Cell Analyzer) and are shown in Figures 6a to 6h.

[0280] Specifically, the expression efficiency of lung immune cells was confirmed following intratracheal administration of PBS (DPBS (Dulbecco's Phosphate-Buffered Saline)) and each experimental example as a control group indicated on the x-axis of Figures 6a to 6h, and the expression efficiency was confirmed in order in alveolar macrophages, neutrophils, B cells, T cells, monocytes, NK cells, dendritic cells (DC), and eosinophils.

[0281] As confirmed in FIGS. 6a to 6h, the composition of the present invention showed superior expression efficiency in lung immune cells compared to a comparative example that did not contain the selective organ-targeted lipid of the present invention.

[0282]

[0283] Although preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements by those skilled in the art using the basic concept of the present invention as defined in the following claims also fall within the scope of the present invention.

Claims

1. Ionizable lipid; Selective Organ Targeting lipid; Cholesterol; and A composition comprising PEG lipid (Polyethylene glycol lipid).

2. In Claim 1, The above composition is a composition further comprising a helper lipid.

3. In Claim 1, A composition characterized in that the ionized lipid comprises 1 to 10 nitrogen atoms and 1 to 10 biodegradable bonds.

4. In Claim 1, The above ionized lipid includes a pyrazole structure or a diazabicyclo structure, and A composition characterized by comprising 1 to 10 ester bonds.

5. In Claim 1, A composition characterized in that the above-mentioned ionized lipid is selected from the group consisting of: (1) bis(2-propylhexyl)6,6'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))dihexanoate; (2) bis(2-propylhexyl)8,8'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))dioctanoate; (3) bis(2-ethylpentyl)4,4'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))dibutyrate; (4) bis(2-ethylpentyl)6,6'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))dihexanoate; (5) bis(2-ethylpentyl)8,8'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))dioctanoate; (6) (((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(methylene))bis(propane-2,1,3-triyl)tetrahexanoate; (7) (((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(methylene))bis(propane-2,1,3-triyl)tetraoctanoate; (8) (((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(methylene))bis(propane-2,1,3-triyl) tetrakis(decanoate); (9) di(henicosan-10-yl)3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)methyl)azandyl)dipropionate; (10) di(pentadecan-7-yl)3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)dipropionate; (11) 1,1'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(tetradecane-2-ol); (12) (((1-(2-(bis(6-((2-hexyldecanoyl)oxy)hexyl)amino)ethyl)-1H-pyrazole-4-yl)methyl)azandil)bis(hexane-6,1-diyl)bis(2-hexyldecanoate); (13) di((Z)-non-2-en-1-yl)9,9'-(((1-(2-(bis(9-(((Z)-non-2-en-1-yl)oxy)-9-oxononyl)amino)ethyl)-1H-pyrazol-4-)methyl)azandyl)dinonanoate; (14) N-((1-(2-(ditetradecylamino)ethyl)-1H-pyrazole-4-yl)methyl)-N-tradecyltetradecane-1-amine; (15) (((((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(ethane-2,1-diyl))bis(azantryl))tetrakis(hexane-6,1-diyl)tetrakis(2-hexyldecanoate); (16) (((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)azandil)bis(hexane-6,1-diyl)bis(2-hexyldecanoate); (17) di(pentadecan-7-yl)6,6'-(((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)azandyl)dihexanoate; (18) (((((1-(2-hydroxyethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(ethane-2,1-diyl))bis(azantryl))tetrakis(hexane-6,1-diyl)tetrakis(2-hexyldecanoate); (19) (((((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(ethane-2,1-diyl))bis(azantryl))tetrakis(hexane-6,1-diyl)tetrakis(2-hexyldecanoate); (20) di((Z)-non-2-en-1-yl)9,9'-(((1-(2-(bis(2-hydroxyethyl)amino)ethyl)-1H-pyrazol-4-yl)methyl)azandyl)dinonanoate; (21) didodecyl 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)dipropionate; (22) Didodecyl 3,3'-(((1-(2-hydroxyethyl)-1H-pyrazole-4-yl)methyl)azandyl)dipropionate; (23) didodecyl 3,3'-(((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)azandiyl)dipropionate; (24) 11-((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)-24-hexyl-8,14,23-trioxo-7,15,22-trioxa-11-azadotriacontyl 2-hexyl undecanoate; (25) 24-hexyl-11-((1-(2-hydroxyethyl)-1H-pyrazole-4-yl)methyl)-8,14,23-trioxo-7,15,22-trioxa-11-azadotriacontyl 2-hexyl undecanoate; (26) 24-hexyl-11-((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)-8,14,23-trioxo-7,15,22-trioxa-11-azadotriacontyl 2-hexyl undecanoate; (27) Dioctyl 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)methyl)azandyl)dipropionate; (28) Dihexadecyl 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)dipropionate; (29) ((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(butane-4,1-diyl)bis(2-hexyldecanoate); (30) di((Z)-non-2-en-1-yl) 9,9'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)dinonanoate; (31) di((Z)-non-2-en-1-yl) 9,9'-(((1-(2-hydroxyethyl)-1H-pyrazole-4-yl)methyl)azandyl)dinonanoate; (32) di((Z)-non-2-en-1-yl) 9,9'-(((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)azandyl)dinonanoate; (33) bis(4-(propionyloxy)butyl) 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl) dipropionate; (34) ((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(butane-4,1-diyl)dipentanoate; (35) ((3,3'-(((1-(2-(dimethylamino)ethyl)- 1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(butane-4,1-diyl) diheptanoate; (36) ((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(butane-4,1-diyl)dinonanoate; (37) ((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(butane-4,1-diyl) diundecanoate; (38) ((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(ethane-2,1-diyl) diheptanoate; (39) ((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))bis(propane-3,1-diyl)dihexanoate; (40) ((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandil)bis(propanoyl))bis(oxy))bis(pentane-5,1-diyl)dibutyrate; (41) bis(2-ethylhexyl)4,4'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandil)bis(propanoyl))bis(oxy))dibutyrate; (42) bis(2-ethylhexyl)6,6'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandil)bis(propanoyl))bis(oxy))dihexanoate; (43) bis(2-ethylhexyl)8,8'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandil)bis(propanoyl))bis(oxy))dioctanoate; (44) bis(2-propylhexyl)4,4'-((3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)bis(propanoyl))bis(oxy))dibutyrate; (45) (2R,2'R)-1,1'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandiyl)bis(decan-2-ol); (46) (S)-1-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)((R)-2-hydroxydecyl)amino)decane-2-ol; (47) (2R,2'R)-1,1'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandiyl)bis(dodecane-2-ol); (48) (S)-1-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)((R)-2-hydroxydodecyl)amino)dodecane-2-ol; (49) (2R,2'R)-1,1'-(((1-(2-hydroxyethyl)-1H-pyrazole-4-yl)methyl)azandiyl)bis(dodecane-2-ol); (50) (S)-1-(((R)-2-hydroxydodecyl)((1-(2-hydroxyethyl)-1H-pyrazole-4-yl)methyl)amino)dodecane-2-ol; (51) di(pentadecan-7-yl)3,3'-(((1-(2-(bis(3-oxo-3-(pentadecan-7-yloxy)propyl)amino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)dipropionate; (52)((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl)) tetrakis(propaneoil))tetrakis(oxy))tetrakis(butane-4,1-diyl)tetranonanoate; (53) tetrakis(2-ethylhexyl) 3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrapropionate; (54) tetrakis(4-(2-cyclohexylacetoxy)butyl) 3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrapropionate; (55) ((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy)) tetrakis(butane-4,1-diyl)tetraheptanoate; (56) ((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl)) tetrakis(propaneoil))tetrakis(oxy))tetrakis(ethane-2,1-diyl)tetraheptanoate; (57) ((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl)) tetrakis(propaneoil))tetrakis(oxy))tetrakis(butane-4,1-diyl)tetratridecanoate; (58) Tetrakis(2-ethylhexyl) 4,4',4'',4''-((3,3',3'',3''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrabutyrate; (59) Tetrakis(2-ethylhexyl) 6,6',6'',6''-((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrahexanoate; (60) Tetrakis(2-propylhexyl) 4,4',4'',4''-((3,3',3'',3''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrabutyrate; (61) Tetrakis(2-ethylpentyl) 4,4',4'',4'''-((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrabutyrate; (62) Tetrakis(2-ethylpentyl) 6,6',6'',6'''-((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrahexanoate; (63) tetra((Z)-non-2-en-1-yl) 9,9',9'',9'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryyl))tetranonanoate; (64) (((3,3',3'',3'''-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrakis(methylene))tetrakis(propane-2,1,3-triyl)octahexanoate; (65) di(henicosan-10-yl) 3,3'-(((2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(methylazandyl))dipropionate; (66) ((3,3'-((3-(5-(3-hydroxypropyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)propyl)azandyl)bis(propaneoil))bis(oxy))bis(hexane-6,1-diyl)bis(2-hexyldecanoate.

6. In Claim 1, The above ionized lipids are heptadecan-9-yl 8-[2-hydroxyethyl-(6-oxo-6-undecooxyhexyl)amino]octanoate, (6Z,9Z,28Z,31Z)-hephtatriaconta-6,9,28,31-tetraene-19-yl4-(dimethylamino)butanoate, di(pentadecan-7-yl)3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azandyl)dipropionate, di(pentadecan-7-yl)6,6'-(((1-(4-hydroxybutyl)-1H-pyrazole-4-yl)methyl)azandyl)dihexanoate, tetrakis(2-ethylhexyl) 3,3',3'',3'''-(((2,5-Diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrapropionate, tetrakis(2-ethylpentyl) 4,4',4'',4'''-((3,3',3'',3'''-(((2,5-Diazabicyclo[2.2.1]heptane-2,5-diyl)bis(propane-3,1-diyl))bis(azantryl))tetrakis(propaneoil))tetrakis(oxy))tetrabutyrate, di(tridecan-6-yl) 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)dipropionate, Di(heptadecan-8-yl) 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)dipropionate, di(nonadecan-9-yl) 3,3'-(((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)dipropionate, di(pentadecan-7-yl) 3,3'-(((1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)dipropionate, (((1-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)methyl)azanediyl)bis(ethane-2,1-diyl)bis(2-hexyldecanoate) and combinations thereof A composition selected from the military.

7. In Claim 1, A composition characterized in that the above-mentioned selective long-term target lipid is represented by the following chemical formula 1: [Chemical Formula 1] In the above chemical formula 1, R1 and R2 are each independently a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C2 to C30 alkenyl group, or a substituted or unsubstituted C2 to C30 alkynyl group, and X and Y are each independently -COO-, -OCO-, -NHCO-, -CONH-, -CHOH-, a substituted or unsubstituted C1 to C5 alkylene group, a substituted or unsubstituted C2 to C5 alkenylene group or a substituted or unsubstituted C2 to C5 alkynylene group, and Z is -O-, -N + R4R5-, -COO-, -OCO-, -NHCO-, -CONH-, single bond, substituted or unsubstituted C1 to C5 alkylene group, substituted or unsubstituted C2 to C5 alkenylene group or substituted or unsubstituted C2 to C5 alkynylene group, and R4 and R5 are each independently hydrogen or a substituted or unsubstituted C1 to C5 alkyl group, and R3 is -COOH, -OH, -C5H 10 N + O2 - or -C7H4O2 - And, m, n, o, and p are each independently integers from 0 to 10.

8. In Claim 1, The above-mentioned selective long-term target lipid is a composition selected from the group consisting of ceramide (C18:1 Ceramide (d18:1 / 18:1), N-oleoyl-D-erythro-sphingosine), DGTS (1,2-dipalmitoyl-sn-glycero-3-O-4'-(N,N,N-trimethyl)-homoserine), DOBAQ (N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propane-1-amine), DHSG (1,5-dihexadecyl N-(3-carboxy-1-oxopropyl)-L-glutamate), 16:0 DGS (1,2-dipalmitoyl-sn-glycero-3-succinate) and combinations thereof.

9. In Claim 1, The above-mentioned selective long-term target lipid is a composition that does not contain phosphate groups.

10. In Claim 1, The above PEG lipid is a composition selected from the group consisting of DMG-PEG2000 (1,2-dimyristoyl-lac-glycero-3-methoxypolyethylene glycol-2000), DSPE-PEG2000 (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000]), ceramide-PEG2000 (N-palmitoyl-sphingosine-1-{succinyl[methoxy(polyethylene glycol)2000]}) and combinations thereof.

11. In Claim 2, The above-mentioned helper lipid is a phospholipid composition.

12. In Claim 1, The above composition is a composition having a particle size (Z-average) of 50 nm to 300 nm.

13. In Claim 1, The above composition comprises, based on the sum of mol% of ionized lipids, selective organ target lipids, cholesterol, and PEG lipids, 10 mol% to 60 mol% of ionized lipids; 5 mol% to 45 mol% of selective organ target lipids; 20 mol% to 65 mol% of cholesterol; and 0.9 mol% to 5 mol% of PEG lipids.

14. In Claim 2, The above composition comprises 3 mol% to 20 mol% of helper lipids based on the sum of mol% of ionized lipids, selective organ target lipids, cholesterol, PEG lipids, and helper lipids.

15. In any one of claims 1 to 14, The above composition is a composition further comprising nucleic acid.

16. In Claim 15, The above nucleic acid is a composition selected from the group consisting of mRNA, siRNA, aiRNA, miRNA, dsRNA, shRNA, lncRNA, saRNA, rRNA, RNA, DNA, cDNA, plasmid, aptamer, tRNA, piRNA, circRNA, antisense oligonucleotide, ribozyme, PNA, DNAzyme, and combinations thereof.

17. In Claim 15, The above composition is a composition that is targeted and delivered to extrahepatic tissues.

18. In Claim 15, The above composition is a composition that is targeted and delivered to the spleen or immune cells.

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