Lung-targeting lipid composition, pharmaceutical composition comprising same, and uses thereof

Abstract

The invention relates to the field of medical biology, and discloses a lung-targeting lipid composition, a pharmaceutical composition containing the same and application of the lung-targeting lipid composition and the pharmaceutical composition. Compared with the traditional LNP, the lipid composition provided by the invention omits one component, and has higher cell transfection efficiency through the cooperation of the components. In addition, the lipid composition provided by the invention also has good lung targeting property, and fills the blank of the LNP delivery system in the aspect of targeting property of other organs except the liver, especially the lung targeting property.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical biology, and more specifically to a lipid composition with lung-targeting properties, pharmaceutical compositions comprising the same, and their uses. Background Technology

[0002] Lipid nanoparticles (LNPs) have attracted widespread attention as a key technology for delivering mRNA vaccines. For mRNA to function in vivo, a safe, efficient, and stable delivery system is needed to protect nucleic acids from degradation and allow for cellular uptake and intracellular release of mRNA. LNPs can load various drugs, including small molecules, peptides, and nucleic acids, into their cavities, protecting these drugs from destructive proteases and allowing them to cross the cell membrane. The safety of LNPs has been validated in COVID-19 mRNA vaccines.

[0003] Drug delivery technology has long been considered the "last mile" of drug development. For mRNA vaccines, nucleic acid drugs, gene editing, and cell therapies, optimizing the drug itself and conventional drug delivery systems is often insufficient to address the issue of drug-likeness. In such cases, delivery technology becomes particularly important and an indispensable part of these new technologies.

[0004] LNPs typically consist of four components: lipids (also known as ionizable lipids), phospholipids, cholesterol, and PEGylated lipids. Unfortunately, clinical studies have shown that LNPs accumulate in the liver, so most current LNP delivery systems are liver-targeted, but the effective delivery to organs outside the liver (such as the lungs and kidneys) remains a problem to be solved. Summary of the Invention

[0005] The purpose of this invention is to overcome the problems existing in the prior art, such as the lack of means to effectively deliver active pharmaceutical ingredients (such as nucleic acids, proteins, etc.) to the lungs, and to provide a lipid composition with lung targeting, a pharmaceutical composition containing the same, and their uses. The lipid composition provided by this invention, by selecting specific types and structures of lipids and combining them in a certain proportion, has advantages such as high cell transfection efficiency and effective targeting of the lungs.

[0006] To achieve the above objectives, the present invention provides a lipid composition with lung-targeting properties, characterized in that the lipid composition comprises cationic lipids and polyethylene glycol-modified lipids, wherein the molar ratio of the cationic lipids to the polyethylene glycol-modified lipids is (40-500):1; The cationic lipid is provided by cationic lipid A and cationic lipid B, wherein cationic lipid A has the structure shown in formula (I). Formula (I), Where p is 1 or 2; One or two of R1, R2, and R3 are selected from secondary or tertiary amines, and the rest are each independently selected from C3-C4 amines. 30 Straight-chain or branched saturated or unsaturated hydrocarbon groups; L1 and L2 are each independently selected from single bonds, or substituted or unsubstituted C1-C bonds. 20 Saturated or unsaturated alkylene groups; Optionally, each of the q methylene groups in L1 and / or L2 is independently replaced by -O-, -C(O)- or -C(O)O-, where q is an integer from 0 to 10; L1 and / or L2 are selected from substituted C1-C 20 When alkylene is saturated or unsaturated, the substituents are selected from hydroxyl, mercapto, and C1-C6 groups. 20 A combination of one or more alkyl groups; L3 is selected from substituted or unsubstituted C1-C. 10 Alkylene; L3 is selected from the substituted C1-C 10 When alkylene, the substituents are selected from C1-C1. 20 A combination of one or more of alkyl groups and C3-C8 cycloalkyl groups; X1, X2 and X4 are each independently selected from -C(O)-, -C(O)-NH-, -C(O)-S-, -C(O)-O-, -O-, -S- or -NH-; X3 is selected from -NH-, -S-, or -O-.

[0007] A second aspect of the present invention provides the use of the lipid composition described in the first aspect in improving the organ targeting of a medicament.

[0008] A third aspect of the present invention provides the use of the lipid composition described in the first aspect in enhancing the expression of nucleic acids in target organs.

[0009] The fourth aspect of the present invention provides the use of the lipid composition described in the first aspect in improving the cell transfection efficiency of a drug, particularly in vitro cell transfection efficiency.

[0010] A fifth aspect of the present invention provides a pharmaceutical composition comprising a carrier and an active ingredient, wherein the carrier comprises the lipid composition described in the first aspect.

[0011] The sixth aspect of the present invention provides the use of the lipid composition of the first aspect, and / or the pharmaceutical composition of the second aspect, in the preparation of a medicament, wherein the medicament comprises a medicament and / or a vaccine for treating and / or preventing diseases caused by lung infections.

[0012] Through the above technical solution, the present invention can achieve at least the following beneficial effects: This invention, by modifying and simplifying LNP components and based on a novel cationic lipid structure, developed a three-component LNP formulation with significant organ-specific (specifically lung) targeting, achieving mRNA accumulation and translation in the lung. This targeting strategy is applicable to existing LNP systems and holds promise for advancing the development of precision mRNA therapies for various diseases. It also provides new insights for the prevention or treatment of various lung diseases, such as lung cancer, pneumonia, tuberculosis, chronic obstructive pulmonary disease, pulmonary thromboembolism, and pulmonary vasculitis. Attached Figure Description

[0013] Figure 1 The images show the in vivo luminescence results of mice injected with the pharmaceutical composition of Formulation 5 prepared in Example 2 and the organ luminescence results after dissection of the mice.

[0014] Figure 2 The images show the in vivo luminescence results of mice injected with the pharmaceutical composition of formulation 5-2 prepared in Example 2 and the organ luminescence results after dissection of the mice.

[0015] Figure 3 The images show the in vivo luminescence results of mice injected with the pharmaceutical compositions of formulations 5-3 prepared in Example 2 and the organ luminescence results after dissection of the mice. Detailed Implementation

[0016] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0017] In this invention, "cationic lipid" refers to lipid compounds with a positive charge in their structure.

[0018] In this invention, "polyethylene glycol-modified lipids" refers to lipid compounds modified with polyethylene glycol.

[0019] In this invention, the description "optionally" means that the element can be selected, that is, the element may or may not exist. For example, "optionally, R8 is C1-C..." 10 When R8 is a straight-chain or branched alkyl group, at least one C is replaced with N or O, meaning that R8 is C1-C. 10 When the alkyl group is straight-chain or branched, at least one C can be replaced with N or O, or no C can be replaced.

[0020] In this invention, unless otherwise specified, a structure containing carbon-carbon double bonds can be considered to have a double bond portion comprising both cis (E-type) and trans (Z-type) structures.

[0021] The inventors of this invention ingeniously discovered during their research that by adjusting the formulation of the classic LNP, changing the structure of the (at least some) lipid components used, and adjusting the proportions of each component, the organ targeting of the resulting lipid composition can be altered. Through extensive experimentation, the inventors found that by using lipids with specific structures in the lipid composition and combining them with specific types of lipids, the resulting lipid composition can achieve lung targeting while simplifying the four-component formulation of the classic LNP (i.e., reducing the types of lipids used in the formulation).

[0022] Based on this, the first aspect of the present invention provides a lipid composition with lung targeting, the lipid composition comprising cationic lipids and polyethylene glycol-modified lipids, wherein the molar ratio of the cationic lipids to the polyethylene glycol-modified lipids is (40-500):1; The cationic lipid is provided by cationic lipid A and cationic lipid B, wherein cationic lipid A has the structure shown in formula (I). Formula (I), Among them, any one or two of R1, R2, and R3 are selected from secondary or tertiary amines, and the rest are each independently selected from C3-C4. 30 Straight-chain or branched saturated or unsaturated hydrocarbon groups; L1 and L2 are each independently selected from single bonds, or substituted or unsubstituted C1-C bonds. 20 Saturated or unsaturated alkylene groups, wherein each of the q methylene groups in L1 and / or L2 is independently replaced by -O-, -C(O)-, or -C(O)O-, and the substituted or unsubstituted C1-C 20 When a saturated or unsaturated alkylene group has a substituent, the substituent is selected from hydroxyl, mercapto, C1-C6 groups. 20 A combination of one or more alkyl groups; L3 is selected from substituted or unsubstituted C1-C. 10 Alkylene, and the substituted or unsubstituted C1-C 10 When there are substituents on the alkylene group, the substituents are selected from C1-C6. 20 A combination of one or more of alkyl groups and C3-C8 cycloalkyl groups; X1, X2 and X4 are each independently selected from -C(O)-, -C(O)-NH-, -C(O)-S-, -C(O)-O-, -O-, -S- or -NH-, and X3 is selected from -NH-, -S- or -O-; p is 1 or 2; q is an integer between 0 and 10.

[0023] In some preferred embodiments, in formula (I), p is 1 or 2; One or two of R1, R2, and R3 are selected from secondary or tertiary amines, and the rest are each independently selected from C3-C4 amines. 30 Straight-chain or branched saturated or unsaturated hydrocarbon groups; L1 and L2 are each independently selected from single bonds, or substituted or unsubstituted C1-C bonds. 20 Saturated or unsaturated alkylene groups; Optionally, each of the q methylene groups in L1 and / or L2 is independently replaced by -O-, -C(O)- or -C(O)O-, where q is an integer from 0 to 10; L1 and / or L2 are selected from substituted C1-C 20 When alkylene is saturated or unsaturated, the substituents are selected from hydroxyl, mercapto, and C1-C6 groups. 20 A combination of one or more alkyl groups; L3 is selected from substituted or unsubstituted C1-C. 10 Alkylene; L3 is selected from the substituted C1-C 10 When alkylene, the substituents are selected from C1-C1. 20 A combination of one or more of alkyl groups and C3-C8 cycloalkyl groups; X1, X2 and X4 are each independently selected from -C(O)-, -C(O)-NH-, -C(O)-S-, -C(O)-O-, -O-, -S- or -NH-; X3 is selected from -NH-, -S-, or -O-.

[0024] In the lipid composition of the present invention, the molar ratio of cationic lipids to polyethylene glycol-modified lipids can be 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 100:1, 120:1, 130:1, 140:1, 150:1, 160:1, 170:1, 180:1, 190:1, 200:1, 210:1, 220:1, 230:1, 240:1, 250:1, 260:1, 270:1, 28... 0:1, 290:1, 300:1, 310:1, 320:1, 330:1, 340:1, 350:1, 360:1, 370:1, 380:1, 390:1, 400:1, 410:1, 420:1, 430:1, 440:1, 450:1, 460:1, 470:1, 480:1, 490:1, 500:1, or any range consisting of any two of the above ratios, or any intermediate ratio within that range.

[0025] According to a preferred embodiment of the present invention, the molar ratio of cationic lipid A to cationic lipid B is (0.1-5):1. For example, it can be 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, or a range consisting of any two of the above ratios, or any intermediate ratio within that range.

[0026] Preferably, the molar ratio of cationic lipid A to polyethylene glycol-modified lipid is (10-400):1. For example, it can be 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 100:1, 120:1, 130:1, 140:1, 150:1, 160:1, 170:1, 180:1, 190:1, 200:1, 210:1, 220:1, 230:1, 240:1, etc. 1, 250:1, 260:1, 270:1, 280:1, 290:1, 300:1, 310:1, 320:1, 330:1, 340:1, 350:1, 360:1, 370:1, 380:1, 390:1, 400:1, or any range formed by any two of the above ratios, or any intermediate ratio within that range.

[0027] Preferably, the molar ratio of cationic lipid B to polyethylene glycol-modified lipid is (10-400):1. For example, it can be 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 100:1, 120:1, 130:1, 140:1, 150:1, 160:1, 170:1, 180:1, 190:1, 200:1, 210:1, 220:1, 230:1, 240:1, etc. 1, 250:1, 260:1, 270:1, 280:1, 290:1, 300:1, 310:1, 320:1, 330:1, 340:1, 350:1, 360:1, 370:1, 380:1, 390:1, 400:1, or any range formed by any two of the above ratios, or any intermediate ratio within that range.

[0028] According to some preferred embodiments of the present invention, the molar ratio of cationic lipid to polyethylene glycol-modified lipid is (70-500):1.

[0029] According to some preferred embodiments of the present invention, the molar ratio of cationic lipid A, cationic lipid B, and polyethylene glycol-modified lipid in the lipid composition is (50-250):(20-200):1, preferably (50-200):(30-150):1. That is, relative to 1 mol of polyethylene glycol-modified lipid, the lipid composition provided by the present invention may contain 50-250 mol (preferably 50-200 mol) of cationic lipid A and 20-150 mol (preferably 30-100 mol) of cationic lipid B.

[0030] For example, in the lipid composition, the content of cationic lipid A relative to 1 mol of polyethylene glycol-modified lipid can be 50 mol, 60 mol, 70 mol, 80 mol, 90 mol, 100 mol, 110 mol, 120 mol, 130 mol, 140 mol, 150 mol, 160 mol, 170 mol, 180 mol, 190 mol, 200 mol, 210 mol, 220 mol, 230 mol, 240 mol, or 250 mol, or it can be a range consisting of any two of the above values, or any intermediate value within that range.

[0031] For example, in the lipid composition, the content of cationic lipid B relative to 1 mol of polyethylene glycol-modified lipid can be 20 mol, 30 mol, 40 mol, 50 mol, 60 mol, 70 mol, 80 mol, 90 mol, 100 mol, 110 mol, 120 mol, 130 mol, 140 mol, 150 mol, 160 mol, 170 mol, 180 mol, 190 mol, or 200 mol, or it can be a range consisting of any two of the above values, or any intermediate value within that range.

[0032] According to some preferred embodiments of the present invention, in the lipid composition, the content ratio of cationic lipid A, cationic lipid B and polyethylene glycol-modified lipid is (40-80):(20-50):(0.1-2) by molar percentage, and the sum of the contents of cationic lipid A, cationic lipid B and polyethylene glycol-modified lipid is 100.

[0033] In the lipid composition provided by the present invention, the cationic lipid A is the cationic lipid disclosed in CN202410381173.6, and all of its disclosure is incorporated herein by reference.

[0034] According to some preferred embodiments of the present invention, the cationic lipid A has the structure shown in formula (I-1). Equation (I-1), where R1 and R3 are selected from C3-C 30 Straight-chain or branched saturated or unsaturated hydrocarbon groups; L2 is selected from substituted or unsubstituted C1-C. 20 Saturated or unsaturated alkylene groups, wherein q methylene groups in L2 are replaced by -O-, -C(O)-, or -C(O)O-, and the substituted or unsubstituted C1-C 20 When a saturated or unsaturated alkylene group has a substituent, the substituent is selected from hydroxyl, mercapto, C1-C6 groups. 10 A combination of one or more alkyl groups; X1 ’ and X2 ’ Each is independently selected from -O-, -S-, or -NH-.

[0035] In some preferred embodiments, in formula (I-1), R1 and R3 are each independently selected from C3-C 30 Straight-chain or branched saturated or unsaturated hydrocarbon groups; L2 is selected from substituted or unsubstituted C1-C. 20 Saturated or unsaturated alkylene groups; Optionally, q methylene groups in L2 are replaced by -O-, -C(O)-, or -C(O)O-, where q is an integer from 0 to 10; L2 is selected from the substituted C1-C 20 When alkylene is saturated or unsaturated, the substituents are selected from hydroxyl, mercapto, C1-C6 groups. 10 A combination of one or more alkyl groups; X1 ’ and X2 ’ Each is independently selected from -O-, -S-, or -NH-.

[0036] According to some preferred embodiments of the present invention, the cationic lipid A has the structure shown in formula (I-2). Equation (I-2), where X4 ’ Selected from -O-, -S-, or -NH-; R4 and R7 are each independently selected from H, C1-C 14 Alkyl groups, and both R4 and R7 are selected from C1-C6. 14 When alkyl groups are involved, R4 and R7 can form rings; R5 and R6 are each independently selected from H, substituted or unsubstituted C1-C. 20 Alkyl groups, and both R5 and R6 are selected from substituted or unsubstituted C1-C groups. 20 When alkyl groups are involved, R5 and R6 can form rings; Wherein, the substituted or unsubstituted C1-C 20When the alkyl group has substituents, the substituents are selected from C1-C1. 30 A combination of one or more of the following groups: alkyl, C3-C7 cycloalkyl, hydroxyl, amino, acyl, ether, carboxyl, and mercapto; Wherein, when R5 and R6 can form a ring, R5, R6 and the N atom connected to them form a nitrogen heterocycle, or R5 or R6 can form a ring on its own to form a heterocyclic group connected to the N atom; m is an integer from 0 to 9.

[0037] In some preferred embodiments, m in equation (I-2) is an integer from 0 to 9; X4 ’ Selected from -O-, -S-, or -NH-; R4 and R7 are each independently selected from H, C1-C 14 Alkyl groups, and both R4 and R7 are selected from C1-C6. 14 When alkyl groups are involved, R4 and R7 may or may not form a ring; R5 and R6 are each independently selected from H, substituted or unsubstituted C1-C. 20 Alkyl groups, and both R5 and R6 are selected from substituted or unsubstituted C1-C groups. 20 In the case of alkyl groups, R5 and / or R6 may be cyclic or non-cyclic; R5 and / or R6 are selected from the substituted C1-C. 20 When alkyl, the substituents are selected from C1-C2. 30 A combination of one or more of the following groups: alkyl, C3-C7 cycloalkyl, hydroxyl, amino, acyl, ether, carboxyl, and mercapto; When R5 and / or R6 form a ring, R5, R6 and the N atom connected to them form a nitrogen heterocycle, or R5 or R6 forms a ring on its own to form a heterocyclic group connected to the N atom.

[0038] According to some preferred embodiments of the present invention, the cationic lipid A has the structure shown in formula (I-3). Equation (I-3), where R2 and R3 are selected from C3-C 30 Straight-chain or branched saturated or unsaturated hydrocarbon groups; L1 is selected from substituted or unsubstituted C1-C. 20 Saturated or unsaturated alkylene groups, wherein the q methylene groups in L1 are replaced by -O-, -C(O)-, or -C(O)O-, and the substituted or unsubstituted C1-C 20 When a saturated or unsaturated alkylene group has a substituent, the substituent is selected from hydroxyl, mercapto, C1-C6 groups. 10 A combination of one or more alkyl groups; X1' and X2' are each independently selected from -O-, -S-, or -NH-.

[0039] In some preferred embodiments, in formula (I-3), R2 and R3 are each independently selected from C3-C 30 Straight-chain or branched saturated or unsaturated hydrocarbon groups; L1 is selected from substituted or unsubstituted C1-C. 20 Saturated or unsaturated alkylene groups; Optionally, the q methylene groups in L1 are replaced by -O-, -C(O)-, or -C(O)O-; L1 is selected from the substituted C1-C 20 When alkylene is saturated or unsaturated, the substituents are selected from hydroxyl, mercapto, C1-C6 groups. 10 A combination of one or more alkyl groups; X1' and X2' are each independently selected from -O-, -S-, or -NH-.

[0040] According to some preferred embodiments of the present invention, the cationic lipid A has the structure shown in formula (I-4). Formula (I-4), wherein X4' is selected from -O-, -S- or -NH-; R4 and R7 are each independently selected from H, C1-C 14 Alkyl groups, and both R4 and R7 are selected from C1-C6. 14 When alkyl groups are involved, R4 and R7 can form rings; R5 and R6 are each independently selected from H, substituted or unsubstituted C1-C. 20 Alkyl groups, and both R5 and R6 are selected from substituted or unsubstituted C1-C groups. 20 When alkyl groups are involved, R5 and R6 can form rings; Wherein, the substituted or unsubstituted C1-C 20 When the alkyl group has substituents, the substituents are selected from C1-C1. 30 A combination of one or more of the following groups: alkyl, C3-C7 cycloalkyl, hydroxyl, amino, acyl, ether, carboxyl, and mercapto; When R5 and R6 can form a ring, R5, R6 and the N atom connected to them form a nitrogen heterocycle, or R5 or R6 can form a ring on its own to form a heterocyclic group connected to the N atom. m is an integer between 0 and 9.

[0041] In some preferred embodiments, m in equation (I-4) is an integer from 0 to 9; X4' is selected from -O-, -S-, or -NH-; R4 and R7 are each independently selected from H, C1-C 14 Alkyl groups, and both R4 and R7 are selected from C1-C6. 14 In the case of alkyl groups, R4 and R7 may be cyclic or non-cyclic; R5 and R6 are each independently selected from H, substituted or unsubstituted C1-C. 20 Alkyl groups, and both R5 and R6 are selected from substituted or unsubstituted C1-C groups. 20 In the case of alkyl groups, R5 and / or R6 may be cyclic or non-cyclic; R5 and R6 are each independently selected from the substituted C1-C. 20 When alkyl, the substituents are selected from C1-C2. 30 A combination of one or more of the following groups: alkyl, C3-C7 cycloalkyl, hydroxyl, amino, acyl, ether, carboxyl, and mercapto; When R5 and / or R6 form a ring, R5, R6 and the N atom attached to them form a nitrogen heterocycle, or R5 or R6 form a ring on its own to form a heterocyclic group attached to the N atom.

[0042] According to a preferred embodiment of the present invention, R1 is selected from C3-C 30 Straight-chain or branched alkyl groups, C3-C 30 Straight-chain or branched olefin groups and C3-C 30 Any one of straight-chain or branched alkyne groups.

[0043] Preferably, R1 is selected from any of the following structures: , , , , , , , , , , , , , , , , , , , , , , , , and .

[0044] According to a preferred embodiment of the present invention, R2 is selected from C3-C 30 Straight-chain or branched alkyl groups, C3-C 30 Straight-chain or branched olefinic groups or C3-C 30 Any one of straight-chain or branched alkyne groups.

[0045] Preferably, R2 is selected from any of the following structures.

[0046] , , , , , , , , , , , , , , , , , , , , , , , , and .

[0047] In some preferred embodiments of the present invention, when R1 and R2 adopt a structure containing carbon-carbon double bonds, the double bond portion can be cis (E type).

[0048] For example, when R1 and / or R2 are selected from structures containing carbon-carbon double bonds, they can each independently choose any of the following structures: , , , , , .

[0049] In some preferred embodiments of the present invention, when R1 and R2 adopt a structure containing carbon-carbon triple bonds, the triple bond portion can be linear.

[0050] For example, when R1 and / or R2 are selected from structures containing carbon-carbon triple bonds, they can each independently choose any of the following structures: , , .

[0051] According to a preferred embodiment of the present invention, R3 is selected from C4-C. 25 Straight-chain or branched alkyl groups, C4-C 25 Straight-chain or branched olefinic groups or C4-C 25 Any one of straight-chain or branched alkyne groups.

[0052] Preferably, R3 is selected from any of the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0053] In some preferred embodiments of the present invention, when R3 adopts a structure containing carbon-carbon double bonds, its double bond portion can be cis (E type).

[0054] For example, when R3 is selected with a structure containing carbon-carbon double bonds, any of the following structures can be chosen: , , , , , , .

[0055] In some preferred embodiments of the present invention, when R3 adopts a structure containing carbon-carbon triple bonds, its triple bond portion can be linear.

[0056] For example, when R3 is selected with a structure containing a carbon-carbon triple bond, the following structures can be chosen: .

[0057] More preferably, -NR5R6 is selected from any of the following structures: , , , , , , , , , , and .

[0058] More preferably, X1' is -O-; X2' is -O-; X3 is -O- or -S-; X4' is -O-.

[0059] More preferably, L1 and L2 are each independently selected from any of the following structures: , , , , , , , , , , , , , , and .

[0060] More preferably, L3 is selected from any of the following structures: , , , , , , , , , , and .

[0061] According to some preferred embodiments of the present invention, the cationic lipid A has a structure represented by the general formula (H'-ts): General formula (H'-ts) Where L4 is C1-C 10 Straight-chain or branched alkylene groups; R3' is H or a C1-C4 straight-chain or branched alkyl group; R1 and R3 are each independently selected from C3-C 30 Straight-chain or branched saturated or unsaturated hydrocarbon groups; Optionally, at least one alkylene group among L4, R1, and R3 is replaced by at least one of an ether bond, a thioether, an ester group, and an amide. -NR5R6 is selected from any of the following structures (Equation (Y), Equation (X), and Equation (Z)): Formula (Y), In formula (Y), R8 represents H and C1-C. 10 Straight-chain or branched alkyl groups, or R8 is the default; The ring N is a 3-9 membered ring having at least one N atom, wherein one N atom is connected to L4 of the general formula (H'-ts), and the number of N atoms in the ring N is 1-3. Preferably, the framework structure of the ring N is composed of C atoms, N atoms and optional O atoms. R8 is attached to any one or more atoms on ring N that are not attached to L4 of the general formula (H'-ts); Optionally, R8 is C1-C 10 When the alkyl group is straight-chain or branched, at least one of its alkylene groups is replaced by at least one of ether bonds, thioethers, ester groups and amides, and / or at least one of its H groups is replaced by a halogen or a hydroxyl group; Optionally, R8 is C1-C 10 When the alkyl group is straight-chain or branched, at least one C is replaced with N or O; Formula (X), In equation (X), p is any integer between 0 and 5 (e.g., 0, 1, 2, 3, 4, or 5), X is selected from C, N, or O, and R9 is a single bond, or C1-C 10 Straight-chain or branched alkylene groups, R 10 R 10’ and R 9’ Each independently is C1-C 10 Alkyl groups, whether straight-chain or branched; Optional, R 10 R 10’ or R 9’ For C1-C 10 When the alkyl group is straight-chain or branched, at least one of its alkylene groups is replaced by at least one of ether bonds, thioethers, ester groups and amides, and / or at least one of its H groups is replaced by a halogen or a hydroxyl group; Formula (Z), In equation (Z), rings N, X, p, R8, R9, and R 9’ R 10 and R 10’ The definition is the same as in equations (X) and (Y).

[0062] In the general formula (H'-ts), C1-C 10The number of carbon atoms in a straight-chain or branched alkyl / alkylene chain can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or any range of two of the above values, or any intermediate value in that range. The number of carbon atoms in a C1-C4 straight-chain or branched alkyl group can be 1, 2, 3, 4, or any range of two of the above values, or any intermediate value in that range. C3-C 30 Straight-chain or branched saturated or unsaturated hydrocarbon groups refer to straight-chain or branched alkyl, alkenyl, or alkynyl groups having 3-30 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or any two of the above values, or any intermediate value within that range). For C3-C... 30 A straight-chain or branched unsaturated hydrocarbon group, wherein the number of carbon-carbon double bonds and / or carbon-carbon triple bonds may be 1 to 3; When the -NR5R6 portion has the structure of formula (Y) or formula (Z), ring N can be a 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, or 9-membered ring; and if there are 2-3 N atoms in ring N, these N atoms can exist in at least one of the ortho, meta, and para positions on ring N; if there are O atoms on ring N, the O atoms and N atoms can exist in at least one of the ortho, meta, and para positions on ring N.

[0063] Preferably, in the general formula (H'-ts), the -NR5R6 portion can be selected from any of the following structures: , where R a For C1-C 10 Alkyl groups, whether straight-chain or branched; , where R b For H, C1-C 10 Straight-chain or branched alkyl groups, or R b 'NR b ''R b '''-, where R b 'For C1-C 10 Straight-chain or branched alkylene groups, R b '' and R b Each independently constitutes C1-C 10 Alkyl groups, whether straight-chain or branched; , where R c ''' represents a single key, or C1-C 10 Straight-chain or branched alkylene groups, Rc R c 'and R c Each independently constitutes C1-C 10 Alkyl groups, whether straight-chain or branched; , where R d and R d 'Each is independently H or C1-C 10 Alkyl groups, whether straight-chain or branched; Among them, L5, L6, and L7 are each independently a single bond or a C1-C bond. 10 Straight-chain or branched alkylene groups, R e It is an N-containing heterocycle with 3-10 C atoms and 1-3 N atoms, and R e One of the N atoms is connected to L5, and at least one C and / or N a C1-C5 straight-chain or branched alkyl group is further connected to R. e 'For H or C1-C 10 Straight-chain or branched alkyl groups; and Optionally, at least one alkylene group in -NR5R6 is replaced by at least one of an ether bond, a thioether, an ester group, and an amide; and / or, at least one alkyl group in -NR5R6 is replaced by a hydroxyl group.

[0064] For example, according to some preferred embodiments of the present invention, the cationic lipid A may be selected from at least one of the following compounds H'-1 to H'-7: , , , , , , .

[0065] According to some preferred embodiments of the present invention, the cationic lipid A has any one of the structures shown in the following general formula (H-ts): General formula (H-ts) The definitions of R1, R3, and -NR5R6 are the same as in the general formula (H'-ts).

[0066] According to some particularly preferred embodiments of the present invention, in general formulas (H'-ts) and (H-ts), the -NR5R6 portion can be selected from any of the following structures: , , , , , , , , , , and .

[0067] Preferably, the cationic lipid A has a structure shown in any one of the following general formulas (A-ts) to (G-ts): General formula (A-ts); General formula (B-ts); General formula (C-ts); General formula (D-ts); General formula (E-ts); General formula (F-ts); General formula (G-ts); In each of the above general formulas, R1 is independently selected from C3-C 30 Straight-chain or branched saturated or unsaturated hydrocarbon groups (e.g., C3, C4, C5, C6, C7, C8, C9, C10, C11, C20, C30, C40, C50, C60, C70, C80, C90, C10, C110, C120, C130, C140, C150, C160, C170, C18 10 C 11 C 12 C 13 C 14 C 15 C 16 C 17 C 18 C 19 C 20 C 21 C 22 C 23 C 24 C 25 C 26 C 27 C 28 C 29 C 30 Straight-chain saturated or unsaturated hydrocarbon groups, or C4, C5, C6, C7, C8, C9 ... 10 C 11 C 12 C 13 C 14 C 15 C 16 C 17 C 18 C 19 C 20 C21 C 22 C 23 C 24 C 25 C 26 C 27 C 28 C 29 C 30 The structure and preferred structure of the -NR5R6 part (branched saturated or unsaturated hydrocarbon group) are as described in the previous general formula (H'-ts) and general formula (H-ts), and will not be repeated here.

[0068] According to some preferred embodiments of the present invention, the cationic lipid A has any one of the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ， 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ， 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ， 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ， 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ， 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , .

[0069] In this invention, there are no particular restrictions on the specific source of cationic lipid A. It can be obtained through commercial purchase or custom-made means, or it can be prepared by oneself according to existing technology. For example, it can be synthesized by referring to the method described in CN202410381173.6.

[0070] According to a preferred embodiment of the present invention, the cationic lipid B is selected from DOTAP (distearylphosphatidylethanolamine, CAS: 132172-61-3), DDAB (bisdecyldimethylammonium bromide, CAS: 2390-68-3), DOTMA (dioleoylpropyltrimethylammonium chloride, CAS: 104872-42-6), and DOSPA (N-[2-[2,5-bis[(3-aminopropyl)amino]pentanoylamino]ethyl]-N,N-dimethyl-2,3-bis[(Z)-octadecyl-9-en-1-yloxy] [Acrylic acid] propane-1-ammonium chloride tetrahydrochloride, CAS: 282533-23-7, DTAB (dodecyltrimethylammonium bromide, CAS: 1119-94-4), TTAB (tetradecyltrimethylammonium bromide, CAS: 1119-97-7), CTAB (hexadecyltrimethylammonium bromide, CAS: 57-09-0), DDAB (bis(octadecyldimethylammonium bromide), CAS: 3700-67-2), DORI (dimethyl-2-hydroxyethyl-2,3-dioleoyloxypropylammonium bromide, CAS: 1533 12-59-5), DORIE (dimethyl-2-hydroxyethyl-2,3-dioleenooxypropylammonium bromide, CAS: 153312-60-8), DORIE-HP (dimethyl-3-hydroxypropyl-2,3-dioleenooxypropylamine bromide), DORIE-HB (dimethyl-4-hydroxybutyl-2,3-dioleenooxypropylammonium bromide), DORIE-HPC (dimethyl-5-hydroxypentyl-2,3-dioleenooxypropylamine bromide), DPRIE (dimethyl-2-hydroxyethyl-2,3-dihexadecaoxypropylamine bromide) The present invention contains at least one of the following: amine), DSRIE (dimethyl-2-hydroxyethyl-2,3-bisoctadecyloxypropylamine bromide), DMRIE (dimethyl-2-hydroxyethyl-2,3-bistetradecyloxypropylammonium bromide, CAS: 153312-64-2), DOGS (N-(2-argininoyl)-N',N'-bisoctadecylglycine), DOSC (1,2-dioleoyl-3-succinyl-sn-glycerolcholine ester), LPLL (lipid poly-L-lysine), and SA (stearoamide, CAS: 124-26-5). In this invention, there are no particular restrictions on the specific source of cationic lipid B; it can be obtained commercially or through custom-made means, or it can be prepared in-house using existing technologies.

[0071] According to a preferred embodiment of the present invention, the PEGylated lipid is selected from at least one of distearylphosphatidylethanolamine polyethylene glycol, dimyristoylglycerol-rac-methoxy polyethylene glycol, methoxy polyethylene glycol bis(tetradecyl)acetamide, polyethylene glycol-diacylglyceramide, polyethylene glycol-dipalmitoylphosphatidylethanolamine, polyethylene glycol-distosterol glycerol, and polyethylene glycol-diacylglyceramide. In this invention, there is no particular limitation on the specific source of the PEGylated lipid; it can be obtained commercially or through custom-made means, or it can be prepared by the manufacturer using existing technology.

[0072] Preferably, in the PEGylated lipid, the average molecular weight of polyethylene glycol is 1000-5000 (for example, it can be 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, or any range of two of the above values, or any intermediate value within that range). The average molecular weight of polyethylene glycol is also the average number of ethylene oxide units in the polyethylene glycol molecule. For example, PEG-2000 is a polyethylene glycol molecule with an average molecular weight of 2000, which is composed of 2000 ethylene oxide units.

[0073] Preferably, in the lipid composition, the cationic lipid B is DOTAP and / or DDAB, and the polyethylene glycol-modified lipid is DMG-PEG.

[0074] In this invention, cationic lipid A with the aforementioned specific structure is used in combination with cationic lipid B and polyethylene glycol-modified lipid within a specific ratio range. The resulting lipid composition can better target the active pharmaceutical ingredient (e.g., nucleic acid, protein, small molecule compound, etc.) to the lungs. It can be used to develop or prepare drugs related to lung diseases, or for scientific research that requires targeting the active pharmaceutical ingredient to the lungs.

[0075] A second aspect of the present invention provides the use of the lipid composition described in the first aspect in improving the targeting of a drug to a target organ.

[0076] According to a preferred embodiment of the present invention, the target organ is the lung. That is, the lipid composition provided in the first aspect of the present invention can improve the lung targeting of the drug.

[0077] For example, the lipid compositions provided by this invention can be used to prepare drugs (or drug compositions) with higher targeting specificity to target organs.

[0078] A third aspect of the present invention provides the use of the lipid composition described in the first aspect in enhancing the expression of nucleic acids in target organs.

[0079] According to a preferred embodiment of the present invention, the target organ is the lung. By loading the target nucleic acid with the lipid composition provided in the first aspect of the present invention, the target nucleic acid can be introduced into the body and its expression level in the target organ (lung) can be increased.

[0080] For example, the lipid composition provided by the present invention can be used to prepare a drug (or drug composition) that can promote the increase of nucleic acid expression (carried by the lipid composition) in target organs.

[0081] The fourth aspect of the present invention provides the use of the lipid composition described in the first aspect in improving the cell transfection efficiency of a drug, particularly in vitro cell transfection efficiency.

[0082] Improving in vitro cell transfection efficiency means that when a drug is loaded with the lipid composition provided by this invention and then contacted with cells cultured in vitro, the efficiency of drug entry into cells is improved compared with when the lipid composition of this invention is not used or when other existing lipid compositions are used.

[0083] The lipid composition provided by this invention can improve the cell transfection efficiency of drugs both in vivo and in vitro. That is, the lipid composition provided by this invention can be used for therapeutic / diagnostic purposes as well as non-therapeutic purposes. Therapeutic / diagnostic uses may include encapsulating drugs with disease treatment / prevention / diagnostic functions (such as nucleic acids) using the lipid composition provided by this invention, and then administering the encapsulated drug composition to subjects in need. Non-therapeutic uses may include applications in scientific research such as drug screening, detection, and disease mechanism research. For example, encapsulating the drug to be detected (such as nucleic acids) using the lipid composition provided by this invention, and then contacting the encapsulated drug composition with cells used to screen / detect the drug, observing changes in cell morphology, physiological and biochemical aspects, and metabolism after contact to determine the drug's effect.

[0084] A fifth aspect of the present invention provides a pharmaceutical composition comprising a carrier and an active ingredient, wherein the carrier comprises the lipid composition described in the first aspect.

[0085] According to a preferred embodiment of the present invention, the active ingredient includes at least one of nucleic acids, oligonucleotides, small molecule compounds, polypeptides, and proteins.

[0086] Preferably, the nucleic acid includes RNA, DNA, antisense nucleic acid, aptamer, ribozyme, immunostimulatory nucleic acid, or PNA.

[0087] More preferably, the RNA includes at least one of mRNA, rRNA, circRNA, siRNA, saRNA, tRNA, snRNA, antagomir, microRNA inhibitor, microRNA activator, and shRNA.

[0088] Preferably, the active ingredient is nucleic acid.

[0089] According to a particularly preferred embodiment of the present invention, the active ingredient is RNA.

[0090] According to a preferred embodiment of the present invention, the weight ratio of the carrier to the active ingredient is (5-20):1. For example, it can be 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, or any range of any two of the above ratios, or any intermediate ratio within that range. When the weight ratio of the carrier to the active component is within the range of the present invention, the resulting pharmaceutical composition has a better lung-targeting effect, and when the active component is a nucleic acid, the expression of the nucleic acid carried by the pharmaceutical composition in lung cells is enhanced.

[0091] According to a preferred embodiment of the present invention, the pharmaceutical composition further includes excipients, preferably including at least one of buffers, protectants, coating agents, flavoring agents and adjuvants.

[0092] The sixth aspect of the present invention provides the use of the lipid composition of the first aspect, and / or the pharmaceutical composition of the fifth aspect, in the preparation of a medicament, wherein the medicament comprises a medicament and / or a vaccine for treating and / or preventing diseases caused by lung infections.

[0093] The present invention will be described in detail below through embodiments. It should be understood that the following embodiments are only used to further explain and illustrate the content of the present invention by way of example, and are not intended to limit the present invention.

[0094] Unless otherwise specified, the materials and reagents used in the following examples are all commercially available products purchased from legitimate chemical or biological laboratory supply suppliers, and all reagents are of analytical grade.

[0095] Example 1 In this embodiment, cationic lipid A for formulating lipid compositions was synthesized according to the method of CN202410374231.2.

[0096] The following are some exemplary methods for synthesizing compounds: Synthesis of cationic lipid compound D10 Step 1: 41.2 mmol of 13-eicosadecanol (1-1) was dissolved in 100 mL of dichloromethane, followed by the addition of 61.8 mmol of triethylamine and 20.6 mmol of 4-dimethylaminopyridine. 61.8 mmol of 2-bromopropionyl bromide was added dropwise at 30-40 °C. After the addition was complete, the mixture was refluxed and stirred for 4 h to stop the reaction. Water was added, and the mixture was extracted and separated. The organic phase was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and the solvent was evaporated. The residue (intermediates 1-3) was used directly in the next reaction without further treatment.

[0097] Step Two: 26.5 mmol of 2-bromopropionic acid-2-hexyl-1-decyl ester (1-3) was dissolved in 100 mL of N,N-dimethylformamide, and then 39.75 mmol of potassium carbonate was added. The mixture was stirred for 20-30 min, and 29.15 mmol of 1-thioglycerol was added dropwise below 30 °C. After the addition was complete, the mixture was stirred overnight at room temperature. The reaction was stopped the next day, and the mixture was extracted with ethyl acetate after adding 300 mL of water. The aqueous phase was back-extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and the solvent was evaporated. The residue was purified by column chromatography (dichloromethane:methanol = 95:5) to obtain a light yellow oily liquid (intermediate 1-5) with a yield of 56%.

[0098] Step 3: 24.7 mmol of 2-((2,3-dihydroxypropyl)thio)propionic acid-2-hexyl-1-decyl ester (1-5) was dissolved in 100 mL of dichloromethane, and then 37.05 mmol of triethylamine was added. The system was cooled to 0 °C, and 27.2 mmol of octanoyl chloride (1-7) was added dropwise. After the addition was complete, the mixture was stirred for 3 h and the reaction was stopped. Water was added and the mixture was extracted and separated. The organic phase was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and the solvent was evaporated. The residue was purified by column chromatography (n-heptane:ethyl acetate = 90:10) to obtain a light yellow oily liquid (intermediates 1-6). Intermediate #3 was obtained in 62% yield.

[0099] Step Four: 18.8 mmol of 3-((1-((2-hexyldecane)oxy)-1-oxopropyl-2-yl)thio)-2-hydroxypropyl octanoate (1-6) was dissolved in 100 mL of dichloromethane, followed by the addition of 28.2 mmol of N,N'-dicyclohexylcarbodiimide and 0.9 mmol of 4-dimethylaminopyridine. 22.6 mmol of 4-bromobutyric acid (1-8) was added dropwise below 35 °C. After the addition was complete, the mixture was stirred for 4 h, and the reaction was stopped. The system was filtered, the filtrate was concentrated, and the solvent was evaporated. The residue was purified by column chromatography (n-heptane:ethyl acetate = 90:10) to obtain 8.3 g of a pale yellow oily liquid (intermediate 1-9), with a yield of 65%.

[0100] Step 5: Dissolve 7.35 mmol of 2-((4-bromobutyryl)oxy)-3-((1-((2-hexyldecane)oxy)-1-oxopropyl-2-yl)thio)propyl octanoate (1-9) in 25 ml of acetonitrile, then add 14.7 mmol of triethylamine and 12.5 mmol of... 1-(3-(4-methylpiperazin-1-yl)propyl)amino)dec-2-ol (1-10) was heated to 40°C and stirred overnight. The reaction was stopped the next day, and the system was directly concentrated and the solvent was evaporated. The residue was purified by column chromatography (DCM:MeOH=90:10) to obtain 2.1 g of light yellow oily liquid, namely 3-((1-(eicosodecan-13-oxy)-1-oxopropyl-2-yl)thio)-2-((4-((2-hydroxydecyl)(3-(4-methylpiperazin-1-yl)propyl)amino)butyryl)oxy)propyl octanoate (D10), yield 40%.

[0101] The cationic lipid compound D10 was characterized, and the results are as follows: 1 H NMR (400 MHz, CDCl3) δ 5.26 – 5.12 (m, 1H), 4.86 (dd, J = 12.4, 6.2Hz, 1H), 4.41 – 4.28 (m, 1H), 4.23 – 4.05 (m, 2H), 3.56 (s, 1H), 3.42 (p, J =7.1 Hz, 1H), 2.94 – 2.70 (m, 3H), 2.65 – 2.34 (m, 13H), 2.33 – 2.24 (m, 7H), 1.84 – 1.68 (m, 2H), 1.66 – 1.56 (m, 4H), 1.56 – 1.47 (m, 4H), 1.41 (dd, J =10.3, 7.4 Hz, 5H), 1.24 (s, 60H), 0.86 (t, J = 6.6 Hz, 12H). [M+H] + : 1038.60, [1 / 2M+H] + : 520.00.

[0102] Synthesis of cationic lipid compound G12

[0103] G12 Similar to the procedure for D10, the difference lies in replacing 13-eicosadecanol (1-1) in step one with 2-decyltetradecyl-1-ol (11-1), and replacing octanoyl chloride (1-7) in step three with dodecanoyl chloride (3-7). The final product is 3-((1-((2-decyltetradecyl)oxy)-1-oxopropyl-2-yl)thio)-2-((4-((2-hydroxydecyl)(3-(4-methylpiperazin-1-yl)propyl)amino)butyryl)oxy)propyl dodecanoate (G12).

[0104] The cationic lipid compound G12 was characterized, and the results are as follows: 1 H NMR (400 MHz, CDCl3) δ 5.26 – 5.10(m, 1H), 4.37 – 4.28 (m, 1H), 4.20 – 4.05 (m, 1H), 4.03 (d, J = 5.6 Hz, 2H), 3.56 (s, 1H), 3.50 – 3.40 (m,2H), 2.95 – 2.70 (m, 3H), 2.70 – 2.22 (m, 21H), 1.84 – 1.70 (m, 2H), 1.68 –1.54 (m, 5H), 1.50 – 1.38 (m, 5H), 1.26 (s, 68H), 0.87 (t, J = 6.5 Hz, 12H). [M+H] + : 1080.60, [1 / 2M+H] + : 541.00.

[0105] Synthesis of cationic lipid compound B7

[0106] B7 Similar to the procedure for D10, the difference lies in replacing 13-eicosanool (1-1) in step one with 9-heptadecanool (2-1), and replacing 1-(3-(4-methylpiperazin-1-yl)propyl)amino)dec-2-ol (1-10) in step five with 1-((2-hydroxyethyl)amino)dec-2-ol (24-10). The final product is 3-((1-(heptadecane-9-oxy)-1-oxopropyl-2-yl)thio)-2-((4-((2-hydroxydecyl)(2-hydroxyethyl)amino)butyryl)oxy)propyl octanoate (B7).

[0107] The cationic lipid compound B7 was characterized, and the results are as follows: 1H NMR (400 MHz, CDCl3) δ 5.25 – 5.11 (m, 1H), 4.88 (p, J = 6.3 Hz,1H), 4.45 – 4.32 (m, 1H), 4.19 – 4.08 (m, 1H), 3.72 – 3.53 (m, 3H), 3.43 (p,J = 7.8 Hz, 1H), 2.95 – 2.53 (m, 7H) , 2.52 – 2.35 (m, 4H), 2.31 (t, J = 7.5Hz, 2H), 1.87 – 1.76 (m, 2H), 1.66 – 1.49 (m, 6H), 1.43 (dd, J = 9.0, 7.3 Hz,4H), 1.26 (s, 44H), 0.87 (t, J = 6.7 Hz, 12H). [M+H] + : 830.60.

[0108] Synthesis of cationic lipid compound E7

[0109] E7 Similar to the procedure in D10, the difference is that 1-(3-(4-methylpiperazin-1-yl)propyl)amino)dec-2-ol (1-10) in step five is replaced with 1-((2-hydroxyethyl)amino)dec-2-ol (24-10). This ultimately yields 3-((1-((2-hexyldecyl)oxy)-1-oxopropyl-2-yl)thio)-2-((4-((2-hydroxydecyl)(2-hydroxyethyl)amino)butyryl)oxy)propyl octanoate (E7).

[0110] The cationic lipid compound E7 was characterized, and the results are as follows: 1H NMR (400 MHz, CDCl3) δ 5.24 – 5.10 (m, 1H), 4.45 – 4.31 (m, 1H), 4.18 – 4.09 (m, 1H), 4.03 (d, J = 5.7 Hz, 2H), 3.72 – 3.57 (m, 3H), 3.50 – 3.40 (m, 1H), 2.96 – 2.51 (m, 7H), 2.50 – 2.36 (m, 5H), 2.31 (t, J = 7.6 Hz, 2H), 1.87 – 1.77 (m, 2H), 1.69 – 1.55 (m, 3H), 1.48 – 1.40 (m, 4H), 1.27 (d,J = 7.7 Hz, 44H), 0.87 (t, J = 6.5 Hz, 12H). [M+H] + : 816.60.

[0111] Synthesis of cationic lipid compound H10

[0112] H10 Similar to the procedure for D10, the difference lies in replacing 13-eicosalicol (1-1) in step one with n-octanol (38-1), and replacing 1-(3-(4-methylpiperazin-1-yl)propyl)amino)dec-2-ol (1-10) in step five with 1-((2-hydroxyethyl)amino)dec-2-ol (24-10). The final product is 3-((1-(octoxy)-1-oxopropyl-2-yl)thio)-2-((4-((2-hydroxydecyl)(2-hydroxyethyl)amino)butyryl)oxy)propyl octanoate (H10).

[0113] The cationic lipid compound H10 was characterized, and the results are as follows: 1H NMR (400 MHz, CDCl3) δ 5.24 – 5.10 (m, 1H), 4.97 – 4.86 (m, 1H), 4.44 – 4.32 (m, 1H), 4.13 (dt, J = 12.1, 5.7 Hz, 1H), 3.71 – 3.54 (m, 3H),3.46 – 3.35 (m, 1H), 2.95 – 2.50 (m, 7H), 2.49 – 2.34 (m, 4H), 2.31 (t, J =7.5 Hz, 2H), 1.84 – 1.74 (m, 2H), 1.66 – 1.54 (m, 3H), 1.53 – 1.37 (m, 6H),1.33 – 1.19 (m, 30H), 0.87 (t, J = 6.5 Hz, 9H). [M+H] + : 704.40.

[0114] Synthesis of cationic lipid compound H3

[0115] H3 Similar to the procedure for D10, the difference lies in replacing 13-eicosanool (1-1) in step one with n-octanol (38-1), replacing octanoyl chloride (1-7) in step three with decanoyl chloride (2-7), and replacing 1-(3-(4-methylpiperazin-1-yl)propyl)amino)dec-2-ol (1-10) in step five with 1-((2-hydroxyethyl)amino)dec-2-ol (24-10). The final result is propyl 3-((1-(octoxy)-1-oxopropyl-2-yl)thio)-2-((4-((2-hydroxydecyl)(2-hydroxyethyl)amino)butyryl)oxy)decanoate (H3).

[0116] The cationic lipid compound H3 was characterized, and the results are as follows: 1H NMR (400 MHz, CDCl3) δ 5.25 – 5.11 (m, 1H), 4.97 – 4.87 (m, 1H), 4.46 – 4.31 (m, 1H), 4.14 (dt, J = 12.0, 5.8 Hz, 1H), 3.71 – 3.56 (m, 3H),3.46 – 3.37 (m, 1H), 2.97 – 2.51 (m, 7H), 2.50 – 2.35 (m, 4H), 2.31 (t, J =7.5 Hz, 2H), 1.87 – 1.77 (m, 2H), 1.65 – 1.55 (m, 3H), 1.53 – 1.39 (m, 6H),1.35 – 1.19 (m, 34H), 0.87 (t, J = 6.7 Hz, 9H). [M+H] + : 732.40.

[0117] Synthesis of cationic lipid compound H24

[0118] H24 Similar to the procedure for D10, the difference lies in replacing 13-eicosalicol (1-1) in step one with n-decanol (40-1), and replacing 1-(3-(4-methylpiperazin-1-yl)propyl)amino)dec-2-ol (1-10) in step five with 1-((2-hydroxyethyl)amino)dec-2-ol (24-10). The final product is 3-((1-(decoxy)-1-oxopropyl-2-yl)thio)-2-((4-((2-hydroxydecyl)(2-hydroxyethyl)amino)butyryl)oxy)propyl octanoate (H24).

[0119] The cationic lipid compound H24 was characterized, and the results are as follows: 1H NMR (400 MHz, CDCl3) δ 5.24 – 5.10 (m, 1H), 4.44 – 4.29 (m, 1H), 4.18 – 4.05 (m, 3H), 3.72 – 3.56 (m, 3H), 3.50 – 3.40 (m, 1H), 2.96 – 2.51(m, 7H), 2.50 – 2.35 (m, 4H), 2.31 (t, J = 7.5 Hz, 2H), 1.88 – 1.74 (m, 2H), 1.69 – 1.55 (m, 3H), 1.49 – 1.39 (m, 5H), 1.35 – 1.11 (m, 34H), 0.87 (t, J =6.8 Hz, 9H). [M+H] + : 732.40.

[0120] Synthesis of cationic lipid compound H18

[0121] H18 Similar to the operation of D10, the difference is that 13-eicosanool (1-1) in step one is replaced with n-decanol (40-1), octanoyl chloride (1-7) in step three is replaced with decanoyl chloride (2-7), and 1-(3-(4-methylpiperazin-1-yl)propyl)amino)dec-2-ol (1-10) in step five is replaced with 1-((2-hydroxyethyl)amino)dec-2-ol (24-10), finally yielding 3-((1-(decoxy)-1-oxopropyl-2-yl)thio)-2-((4-((2-hydroxydecyl)(2-hydroxyethyl)amino)butyryl)oxy)decanoic acid propyl ester (H18).

[0122] The cationic lipid compound H18 was characterized, and the results are as follows: 1H NMR (400 MHz, CDCl3) δ 5.25 – 5.10 (m, 1H), 4.45 – 4.29 (m, 1H), 4.17 – 4.08 (m, 3H), 3.72 – 3.57 (m, 3H), 3.50 – 3.40 (m, 1H), 2.96 – 2.52(m, 7H), 2.50 – 2.35 (m, 4H), 2.31 (t, J = 7.5 Hz, 2H), 1.86 – 1.76 (m, 2H), 1.68 – 1.55 (m, 3H), 1.53 – 1.39 (m, 5H), 1.35 – 1.19 (m, 38H), 0.87 (t, J =6.7 Hz, 9H). [M+H] + : 760.40.

[0123] Synthesis of cationic lipid compound B12

[0124] B12 Similar to the procedure for D10, the difference lies in replacing 13-eicosanool (1-1) in step one with 9-heptadecanool (2-1), and replacing octanoyl chloride (1-7) in step three with dodecanoyl chloride (3-7). The final product is 3-((1-(heptadecane-9-oxy)-1-oxopropyl-2-yl)thio)-2-((4-((2-hydroxydecyl)(3-(4-methylpiperazin-1-yl)propyl)amino)butyryl)oxy)propyl dodecanoate (B12).

[0125] The cationic lipid compound B12 was characterized, and the results are as follows: 1 H NMR (400 MHz, CDCl3) δ 5.26– 5.10 (m, 1H), 4.88 (p, J = 6.2 Hz,1H), 4.38 – 4.28 (m, 1H), 4.17 – 4.10 (m, 1H), 3.57 (s, 1H), 3.42 (p, J = 7.1Hz, 1H), 2.94 – 2.70 (m, 3H), 2.65 – 2.24 (m, 21H), 1.85 – 1.70 (m, 2H), 1.68– 1.49 (m, 8H), 1.42 (dd, J = 10.3, 7.3 Hz, 5H), 1.26 (s, 52H), 0.87 (t, J =6.6 Hz, 12H). [M+H] + : 982.60, [1 / 2M+H] + : 492.00.

[0126] Synthesis of cationic lipid compound C11

[0127] C11 Similar to the procedure for D10, the difference lies in replacing 13-eicosanool (1-1) in step one with 11-eicosanool (4-1), and replacing octanoyl chloride (1-7) in step three with decanoyl chloride (2-7). The final product is propyl 3-((1-(eicosano-11-oxy)-1-oxopropyl-2-yl)thio)-2-((4-((2-hydroxydecyl)(3-(4-methylpiperazin-1-yl)propyl)amino)butyryl)oxy)decanoate (C11).

[0128] The cationic lipid compound C11 was characterized, and the results are as follows: 1 H NMR (400 MHz, CDCl3) δ 5.26 – 5.10 (m, 1H), 4.87 (dd, J = 12.4, 6.2Hz, 1H), 4.41 – 4.28 (m, 1H), 4.23 – 4.05 (m, 2H), 3.56 (s, 1H), 3.42 (p, J =7.1 Hz, 1H), 2.94 – 2.70 (m, 3H), 2.65 – 2.34 (m, 13H), 2.33 – 2.24 (m, 7H), 1.84 – 1.68 (m, 2H), 1.66 – 1.56 (m, 4H), 1.56 – 1.47 (m, 4H), 1.41 (dd, J =10.3, 7.4 Hz, 5H), 1.25 (s, 56H), 0.86 (t, J = 6.6 Hz, 12H). [M+H] + : 1010.60, [1 / 2M+H] + : 506.00.

[0129] Example 2 This embodiment illustrates the preparation of a pharmaceutical composition using the lipid composition of the present invention as a carrier and mRNA as the active ingredient.

[0130] (a) Pharmaceutical compositions containing different cationic lipids A Preparation method: Cationic lipid compound A, cationic lipid compound B (specifically DOTAP), and DMG-PEG (specifically DMG-PEG2000) were dissolved in ethanol according to the molar ratio in Table 1 to obtain the ethanol phase. Firefly luciferase mRNA (Fluc mRNA) was diluted in citrate buffer (10 mM, pH=4) to obtain the aqueous phase solution. According to the mass ratio of lipid composition to mRNA in Table 1, the calculated amount of ethanol phase and aqueous phase solution were rapidly mixed at a 1 / 3 volume ratio, allowed to stand for 20 min to obtain LNP, ultrafiltered and centrifuged 3 times, and finally 1×PBS was added to the required sample volume to obtain the LNP delivery system. In Table 1, the "content" of each lipid refers to the number of parts (molar parts) calculated by molar amount. For example, in formulation 1 in Table 1, the content of cationic lipid A is 150 parts, the content of cationic lipid B is 70 parts, and the content of DMG-PEG is 1 part.

[0131] Table 1. Formulation of mRNA drug compositions

[0132] (ii) Pharmaceutical compositions containing different cationic lipids B or polyethylene glycol-modified lipids Following the method in Experiment (I), lipid compositions were prepared according to the types and amounts (molar parts) of lipids in Table 2. Then, drug compositions were prepared according to a weight ratio of 10:1 between the lipid composition and Fluc mRNA.

[0133] Table 2

[0134] Example 3 The biotoxicity of the LNP delivery system prepared in Example 2 was determined using the following methods: Human ovarian cancer cells IGROV1 were cultured in 1640 medium containing 10% fetal bovine serum and seeded at a density of 10,000 cells / well in 96-well plates, and incubated in a CO2 cell culture incubator for 24 h. Then, LNPs containing Flux mRNA prepared in Example 2 were added to the cells, with the amount of LNP added per well being 25 ng / well, and incubation continued for another 24 h. Cell viability was determined using an AlamarBlue assay kit. After adding AlamarBlue assay reagent, incubation continued for 2 h, and detection was performed using a multi-mode microplate reader with the excitation wavelength set to 530 nm and the emission wavelength set to 590 nm. Cell viability was calculated using cells in wells without LNPs as a control, and the results are shown in Table 3. A cell viability greater than 80% was considered to indicate that the LNP delivery system was non-cytotoxic.

[0135] Table 3

[0136] Testing showed that the drug compositions prepared in Example 2 were all non-cytotoxic (the results showed that the cell survival rate was all above 80%).

[0137] Example 4 This example illustrates the organ-targeting properties of the pharmaceutical composition.

[0138] Experimental Methods: Six- to eight-week-old C57BL / 6 mice were injected intravenously with LNPs containing luciferase mRNA (0.25 mg / kg) (i.e., the drug composition prepared in Example 2). Six hours after injection, the mice were intraperitoneally injected with D-luciferin potassium substrate (100 μL, 30 mg / mL). The bioluminescence intensity of the mouse body and various (dissected) organs was measured using a small animal in vivo imaging system to determine the expression of luciferase protein in different organs after administration of different drug compositions. The results of the bioluminescence intensity of the lungs in mice are detailed in Table 4.

[0139] Table 4

[0140] Figures 1-3 The images sequentially show the in vivo chemiluminescence results in mice injected with the drug compositions of formulations 5, 5-2, and 5-3, and the organ chemiluminescence results after mouse dissection. As can be seen from the images, these formulations exhibit excellent lung targeting, and the mRNA carried in the drug compositions is highly expressed in the lungs. While the mRNA carried in the drug compositions of comparative formulations D1 and D2 also shows high expression in the lungs, it is also highly expressed in organs such as the spleen and liver. Compared to using the lipid composition of this invention as a carrier, the lung targeting of the drug compositions is still insufficient (poor organ targeting specificity).

[0141] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A lipid composition with lung-targeting properties, characterized in that, The lipid composition comprises cationic lipids and polyethylene glycol-modified lipids, wherein the molar ratio of the cationic lipids to the polyethylene glycol-modified lipids is (40-500):1; The cationic lipid is provided by cationic lipid A and cationic lipid B, wherein cationic lipid A has the structure shown in formula (I). Formula (I), Where p is 1 or 2; One or two of R1, R2, and R3 are selected from secondary or tertiary amines, and the others are each independently selected from C3-C4. 30 Straight-chain or branched saturated or unsaturated hydrocarbon groups; L1 and L2 are each independently selected from single bonds, or substituted or unsubstituted C1-C bonds. 20 Saturated or unsaturated alkylene groups; Optionally, each of the q methylene groups in L1 and / or L2 is independently replaced by -O-, -C(O)- or -C(O)O-, where q is an integer from 0 to 10; L1 and / or L2 are selected from substituted C1-C 20 When alkylene is saturated or unsaturated, the substituents are selected from hydroxyl, mercapto, and C1-C6 groups. 20 A combination of one or more alkyl groups; L3 is selected from substituted or unsubstituted C1-C. 10 Alkylene; L3 is selected from the substituted C1-C 10 When alkylene, the substituents are selected from C1-C1. 20 A combination of one or more of alkyl groups and C3-C8 cycloalkyl groups; X1, X2 and X4 are each independently selected from -C(O)-, -C(O)-NH-, -C(O)-S-, -C(O)-O-, -O-, -S- or -NH-; X3 is selected from -NH-, -S-, or -O-.

2. The lipid composition according to claim 1, wherein, The molar ratio of cationic lipids to polyethylene glycol-modified lipids is (70-500):1; Preferably, the molar ratio of cationic lipid A to cationic lipid B is (0.1-5):1; Preferably, the molar ratio of cationic lipid A to polyethylene glycol-modified lipid is (10-400):1; Preferably, the molar ratio of cationic lipid B to polyethylene glycol-modified lipid is (10-400):1; More preferably, in the lipid composition, the molar ratio of cationic lipid A, cationic lipid B and polyethylene glycol-modified lipid is (50-250):(20-200):1; More preferably, in the lipid composition, the content ratio of cationic lipid A, cationic lipid B and polyethylene glycol-modified lipid is (40-80):(20-50):(0.1-2) by molar percentage, and the sum of the contents of cationic lipid A, cationic lipid B and polyethylene glycol-modified lipid is 100.

3. The lipid composition according to claim 1 or 2, wherein, Cationic lipid A has the structure shown in formula (I-1). Formula (I-1), Among them, R1 and R3 are each independently selected from C3-C 30 Straight-chain or branched saturated or unsaturated hydrocarbon groups; L2 is selected from substituted or unsubstituted C1-C. 20 Saturated or unsaturated alkylene groups; Optionally, q methylene groups in L2 are replaced by -O-, -C(O)-, or -C(O)O-, where q is an integer from 0 to 10; L2 is selected from the substituted C1-C 20 When alkylene is saturated or unsaturated, the substituents are selected from hydroxyl, mercapto, C1-C6 groups. 10 A combination of one or more alkyl groups; X1 ’ and X2 ’ Each is independently selected from -O-, -S-, or -NH-; And / or, cationic lipid A has the structure shown in formula (I-2), Formula (I-2), Where m is an integer from 0 to 9; X4 ’ Selected from -O-, -S-, or -NH-; R4 and R7 are each independently selected from H, C1-C 14 Alkyl groups, and both R4 and R7 are selected from C1-C6. 14 When alkyl groups are involved, R4 and R7 may or may not form a ring; R5 and R6 are each independently selected from H, substituted or unsubstituted C1-C. 20 Alkyl groups, and both R5 and R6 are selected from substituted or unsubstituted C1-C groups. 20 In the case of alkyl groups, R5 and / or R6 may be cyclic or non-cyclic; R5 and / or R6 are selected from the substituted C1-C. 20 When alkyl, the substituents are selected from C1-C2. 30 A combination of one or more of the following groups: alkyl, C3-C7 cycloalkyl, hydroxyl, amino, acyl, ether, carboxyl, and mercapto; When R5 and / or R6 cyclize, R5, R6 and the N atom connected to them form a nitrogen heterocycle, or R5 or R6 cyclizes on its own to form a heterocyclic group connected to the N atom. And / or, cationic lipid A has the structure shown in formula (I-3), Formula (I-3), Among them, R2 and R3 are each independently selected from C3-C 30 Straight-chain or branched saturated or unsaturated hydrocarbon groups; L1 is selected from substituted or unsubstituted C1-C. 20 Saturated or unsaturated alkylene groups; Optionally, the q methylene groups in L1 are replaced by -O-, -C(O)-, or -C(O)O-; L1 is selected from the substituted C1-C 20 When alkylene is saturated or unsaturated, the substituents are selected from hydroxyl, mercapto, C1-C6 groups. 10 A combination of one or more alkyl groups; X1' and X2' are each independently selected from -O-, -S-, or -NH-; And / or, cationic lipid A has the structure shown in formula (I-4), Formula (I-4), Where m is an integer from 0 to 9; X4' is selected from -O-, -S-, or -NH-; R4 and R7 are each independently selected from H, C1-C 14 Alkyl groups, and both R4 and R7 are selected from C1-C6. 14 In the case of alkyl groups, R4 and R7 may be cyclic or non-cyclic; R5 and R6 are each independently selected from H, substituted or unsubstituted C1-C. 20 Alkyl groups, and both R5 and R6 are selected from substituted or unsubstituted C1-C groups. 20 In the case of alkyl groups, R5 and / or R6 may be cyclic or non-cyclic; R5 and R6 are each independently selected from the substituted C1-C. 20 When alkyl, the substituents are selected from C1-C2. 30 A combination of one or more of the following groups: alkyl, C3-C7 cycloalkyl, hydroxyl, amino, acyl, ether, carboxyl, and mercapto; When R5 and / or R6 form a ring, R5, R6 and the N atom attached to them form a nitrogen heterocycle, or R5 or R6 form a ring on its own to form a heterocyclic group attached to the N atom.

4. The lipid composition according to any one of claims 1-3, wherein, R1 and R2 are each independently selected from C3-C 30 Straight-chain or branched alkyl groups, C3-C 30 Straight-chain or branched alkenyl groups and C3-C 30 Any one of straight-chain or branched alkynyl groups; Preferably, R1 and R2 are each independently selected from any of the following structures: , , , , , , , , , , , , , , , , , , , , , , , , and ; And / or, R3 is selected from C4-C 25 Straight-chain or branched alkyl groups, C4-C 25 Straight-chain or branched olefinic groups or C4-C 25 Any one of straight-chain or branched alkyne groups; Preferably, R3 is selected from any of the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and ; More preferably, -NR5R6 is selected from any of the following structures: , , , , , , , , , , and ; More preferably, X1' is -O-; X2' is -O-; X3 is -O- or -S-; X4' is -O-; More preferably, L1 and L2 are each independently selected from any of the following structures: , , , , , , , , , , , , , , and ; More preferably, L3 is selected from any of the following structures: , , , , , , , , , , and .

5. The lipid composition according to any one of claims 1-4, wherein, The cationic lipid A has the structure shown in the general formula (H'-ts): General formula (H'-ts) Where L4 is C1-C 10 Straight-chain or branched alkylene groups; R3' is H or a C1-C4 straight-chain or branched alkyl group; R1 and R3 are each independently selected from C3-C 30 Straight-chain or branched saturated or unsaturated hydrocarbon groups; Optionally, at least one alkylene group among L4, R1, and R3 is replaced by at least one of an ether bond, a thioether, an ester group, and an amide. -NR5R6 is selected from any of the following structures: Formula (Y), In formula (Y), R8 represents H and C1-C. 10 Straight-chain or branched alkyl groups, or R8 is the default; Ring N is a 3-9 membered ring having at least one N atom, wherein one N atom is connected to L4 of the general formula (H'-ts), and the number of N atoms in ring N is 1-3. Preferably, ring N is composed of C atoms, N atoms and optional O atoms. R8 is attached to any one or more atoms on ring N that are not attached to L4 of the general formula (H'-ts); Optionally, R8 is C1-C 10 When the alkyl group is straight-chain or branched, at least one of its alkylene groups is replaced by at least one of ether bonds, thioethers, ester groups and amides, and / or at least one of its H groups is replaced by a halogen or a hydroxyl group; Optionally, R8 is C1-C 10 When the alkyl group is straight-chain or branched, at least one C is replaced with N or O; Formula (X), In equation (X), p is any integer between 0 and 5, X is selected from C, N, or O, and R9 is a single bond, or C1-C 10 Straight-chain or branched alkylene groups, R 10 R 10’ and R 9’ Each independently is C1-C 10 Alkyl groups, whether straight-chain or branched; Optional, R 10 R 10’ or R 9’ For C1-C 10 When the alkyl group is straight-chain or branched, at least one of its alkylene groups is replaced by at least one of ether bonds, thioethers, ester groups and amides, and / or at least one of its H groups is replaced by a halogen or a hydroxyl group; Formula (Z), In equation (Z), rings N, X, p, R8, R9, and R 9’ R 10 and R 10’ The definition is the same as in equations (X) and (Y); Preferably, -NR5R6 is selected from any of the following structures: , , , , , , , , , , and ; Preferably, the cationic lipid A has the general formula (the structure shown in H-ts). General formula (H-ts) The definitions of R1, R3, and -NR5R6 are the same as in the general formula (H'-ts); More preferably, the cationic lipid A has any one of the following structures: 、 、 、 、 、 、 ， 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ， 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ， 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ， 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ， 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ， 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ， 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ， 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 6. The lipid composition according to claim 1, wherein, The cationic lipid B is selected from at least one of DOTAP, DDAB, DOTMA, DOSPA, DTAB, TTAB, CTAB, DORI, DORIE, DTAB, DORIE-HP, DORIE-HB, DORIE-HPC, DPRIE, DSRIE, DMRIE, DOGS, DOSC, LPLL, and SA; And / or, the PEGylated lipid is selected from at least one of distearylphosphatidylethanolamine polyethylene glycol, dimyristoylglycerol-rac-methoxy polyethylene glycol, methoxy polyethylene glycol bis(tetradecyl)acetamide, polyethylene glycol-diacylglyceramide, polyethylene glycol-dipalmitoylphosphatidylethanolamine, polyethylene glycol-distosterol glycerol, and polyethylene glycol-diacylglyceramide; Preferably, in the PEGylated lipid, the average molecular weight of polyethylene glycol is 1000-5000.

7. Use of the lipid composition according to any one of claims 1-6 in improving the targeting of a drug to a target organ.

8. Use of the lipid composition according to any one of claims 1-6 in enhancing the expression of nucleic acids in target organs.

9. The use according to claim 7 or 8, wherein, The target organ is the lung.

10. Use of the lipid composition according to any one of claims 1-6 in improving the cell transfection efficiency of a drug, especially in vitro cell transfection efficiency.

11. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a carrier and an active ingredient, wherein the carrier comprises a lipid composition according to any one of claims 1-6.

12. The pharmaceutical composition according to claim 11, wherein, The active ingredient includes at least one of nucleic acids, oligonucleotides, small molecule compounds, peptides, and proteins; Preferably, the active ingredient is nucleic acid, and more preferably RNA.

13. The pharmaceutical composition according to claim 11 or 12, wherein, The weight ratio of carrier to active ingredient is (5-20):

1.

14. The pharmaceutical composition according to any one of claims 11-13, wherein, The pharmaceutical composition further includes excipients, preferably including at least one of buffers, protectants, coating agents, flavoring agents, and adjuvants.

15. The lipid composition of any one of claims 1-6, and / or the use of the pharmaceutical composition of any one of claims 11-14 in the preparation of a medicament, wherein, The drugs include medications and / or vaccines used to treat and / or prevent diseases caused by lung infections.

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