Ionizable lipid compound and use thereof

Abstract

Disclosed in the present invention is an ionizable lipid compound and a use thereof. The ionizable lipid compound has a structure as represented by formula (I). In the ionizable lipid compound of the present invention, a polyoxa-structure is introduced in combination with a hydroxyl group at the head, so that the lipid compound has good biocompatibility and excellent in vivo mRNA delivery efficiency. The structural design is novel, the proportion of each component of a matched LNP dosage form is appropriate, and animal experiments have demonstrated that the delivery effect reaches an international advanced level of commercialized ionizable lipids and the safety is good.

Description

An ionizable lipid compound and its application Technical Field

[0001] The invention belongs to the field of new preparation materials and relates to an ionizable lipid compound and application thereof. Background Art

[0002] Compared to conventional vaccines, mRNA vaccines offer advantages such as low cost, high production efficiency, and superior safety. They also have the potential to synthesize any protein. Therefore, they hold enormous potential for use against emerging infectious viruses that traditional vaccines are unable to combat. However, their application has been limited by the instability of mRNA molecules, their susceptibility to degradation by RNases, and their low in vivo delivery efficiency. To achieve widespread application, mRNA vaccines require a key focus on delivery technology. To achieve optimal immune efficacy, mRNA vaccines require a suitable delivery vehicle to deliver them into the body. Therefore, developing an efficient and non-toxic delivery system is crucial to their success.

[0003] The most advanced delivery vehicle for mRNA is lipid nanoparticles (LNPs), which typically contain at least ionizable lipids, neutral helper lipids, and phospholipid polyethylene glycol derivatives. Currently, most mRNA vaccines developed in China use ionizable lipids invented by foreign companies that are protected by patent restrictions, limiting their commercial use. Research on the stability of LNP formulations and overall safety assessments is still insufficient.

[0004] Summary of the Invention

[0005] To address the shortcomings of the existing technology, the present invention provides an ionizable lipid compound, its preparation method, and its application. The mRNA-LNP prepared using the novel ionizable lipid compound of the present invention exhibits excellent biocompatibility, high in vivo delivery efficiency, high stability, and good biosafety.

[0006] The purpose of the present invention can be achieved through the following technical solutions:

[0007] An ionizable lipid compound, the structure of which is shown in formula (I):

[0008] wherein m is a positive integer selected from 3 to 7; R1, R2, R3, and R4 groups are each independently -H or -OH; R5, R6, R7, and R8 groups are each independently a straight-chain or branched C8-20 alkyl group, a straight-chain or branched C8-20 alkenyl group, or a straight-chain or branched C8-20 alkynyl group, or at least one C atom of the alkyl, alkenyl, or alkynyl group is optionally replaced by a heteroatom independently selected from O, S, or N.

[0009] As a preference of the present invention, m is 3, 4, 5, 6, or 7; the R1, R2, R3, and R4 groups are each independently -OH; and the R5, R6, R7, and R8 groups are each independently a straight-chain C12, C13, or C14 alkyl group.

[0010] An ionizable lipid compound selected from any one of the following compounds:

[0011] As a preferred embodiment of the present invention, the ionizable lipid compound is selected from any one of the following:

[0012] Application of the ionizable lipid compound of the present invention in the preparation of nanolipid preparations.

[0013] A nano lipid particle composition contains the ionizable lipid compound of the present invention.

[0014] As a preferred embodiment of the present invention, the nano lipid particle composition further comprises one or more of ionizable lipids, neutral lipids, and phospholipid polyethylene glycol derivatives.

[0015] As a preferred embodiment of the present invention, the neutral lipid is selected from any one or two of DOPE and cholesterol.

[0016] As a preferred embodiment of the present invention, the phospholipid polyethylene glycol derivative is selected from the phospholipid polyethylene glycol derivative DMG-PEG 2000.

[0017] As a preferred embodiment of the present invention, the nano lipid particle composition is composed of the ionizable lipid compound of the present invention, cholesterol and the phospholipid polyethylene glycol derivative DMG-PEG 2000.

[0018] As a further preferred embodiment of the present invention, the molar ratio of the ionizable lipid compound: cholesterol: phospholipid polyethylene glycol derivative DMG-PEG 2000 in the nanolipid particle composition is 20-100:15-50:1-3, preferably 40-60:30-50:1-2. In a specific embodiment of the present invention, the molar ratio of the ionizable lipid compound: cholesterol: phospholipid polyethylene glycol derivative DMG-PEG 2000 is 50:38.5:1.5.

[0019] The invention relates to the use of the nano-lipid particle composition in the preparation of mRNA drugs or vaccines. Beneficial effects:

[0020] The ionizable lipid compound of this invention incorporates a polyoxo structure and hydroxyl groups in its head, resulting in excellent biocompatibility and in vivo mRNA delivery efficiency. This novel structural design, coupled with the optimal ratio of components in the LNP dosage form, has been shown in animal studies to achieve delivery performance comparable to or even exceeding that of commercial lipids, placing it at the forefront of the industry.

[0021] The ionizable lipid compound of the present invention has high synthesis efficiency and low cost, and is easy to scale up for production and commercial application.

[0022] The three-component formulation ratio of the LNP of the present invention is different from the four-component formulation range of US Patent No. 8,058,069 under the name of Arbutus and is not limited.

[0023] The delivery effect of the LNP formulation corresponding to the ionizable lipid compound of the present invention is at the same level as SM-102, and partially exceeds SM-102.

[0024] The ionizable lipid compound of the present invention has good stability in the LNP formulation. The accelerated stability at 40°C for one month was detected, and the particle size was slightly increased, while the overall structure was maintained. The mRNA could be well encapsulated in the LNP without leakage.

[0025] The safety of the LNP formulations corresponding to the ionizable lipid compounds of the present invention is significantly better than that of Moderna's SM-102 formulation. After ultra-high-dose intravenous injection, most mice experienced no noticeable discomfort, and some mice in the examples experienced rapid relief of discomfort. However, mice injected with the control group SM-102 formulation died. This demonstrates the excellent safety of the ionizable lipid compounds of the present invention and their corresponding LNP formulations. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 HNMR spectrum of ionizable lipid compound H-1 (CDCl3 solution)

[0027] Figure 2 HNMR spectrum of ionizable lipid compound H-2 (CDCl3 solution)

[0028] Figure 3 HNMR spectrum of ionizable lipid compound H-3 (CDCl3 solution)

[0029] Figure 4 HNMR spectrum of ionizable lipid compound H-4 (CDCl3 solution)

[0030] Figure 5 HNMR spectrum of ionizable lipid compound H-5 (CDCl3 solution)

[0031] Figure 6 HNMR spectrum of ionizable lipid compound H-6 (CDCl3 solution)

[0032] Figure 7 HNMR spectrum of ionizable lipid compound H-7 (CDCl3 solution)

[0033] Figure 8 HNMR spectrum of ionizable lipid compound H-8 (CDCl3 solution)

[0034] Figure 9 HNMR spectrum of ionizable lipid compound H-9 (CDCl3 solution)

[0035] Figure 10 HNMR spectrum of ionizable lipid compound H-10 (CDCl3 solution)

[0036] Figure 11: Animal imaging equipment photographs taken after intramuscular injection of mRNA lipid nanoparticles No. 1-10 and control samples prepared in Example 11 into mice DETAILED DESCRIPTION

[0037] Example 1 Synthesis of ionizable lipid compound H-1:

[0038] To a 50 mL reaction flask equipped with a magnetic separator, 10 mmol of 3,6,9-trioxaundecane-1,11-diamine, 50 mmol of 1,2-epoxytetradecane, and 30 mL of dichloromethane were added sequentially. The reaction tube was heated and stirred at 85°C for 72 hours. After completion of the reaction as monitored by TLC, the reaction mixture was cooled to room temperature and the solvent was removed using a rotary evaporator. The product was separated by thin-layer chromatography (silica gel column, eluent: dichloromethane:methanol:triethylamine (volume ratio = 93:6:1)) to obtain the product H-1 as a pale yellow oil in an 89% yield. The specific reaction formula is as follows:

[0039] The H-1 hydrogen spectrum of the ionizable lipid compound is shown in Figure 1.

[0040] Example 2 Synthesis of ionizable lipid compound H-2:

[0041] To a 50 mL reaction flask equipped with a magnetic separator, 10 mmol of 3,6,9-trioxaundecane-1,11-diamine, 50 mmol of 1,2-epoxyhexadecane, and 30 mL of dichloromethane were added sequentially. The reaction tube was heated and stirred at 85°C for 72 hours. After completion of the reaction as monitored by TLC, the reaction mixture was cooled to room temperature and the solvent was removed using a rotary evaporator. The product was separated by thin-layer chromatography (silica gel column, eluent: dichloromethane:methanol:triethylamine = 93:6:1 by volume) to obtain the milky white oily product H-2 in an 87% yield. The specific reaction formula is as follows:

[0042] The H-2 hydrogen spectrum of the ionizable lipid compound is shown in Figure 2.

[0043] Example 3 Synthesis of ionizable lipid compounds:

[0044] To a 50 mL reaction flask equipped with a magnetic separator, 10 mmol of 3,6,9,12-tetraoxatetradecane-1,14-diamine, 50 mmol of 1,2-epoxytetradecane, and 30 mL of dichloromethane were added sequentially. The reaction tube was heated and stirred at 90°C for 72 hours. After completion of the reaction as monitored by TLC, the reaction mixture was cooled to room temperature and the solvent was removed using a rotary evaporator. The product was separated by thin-layer chromatography (silica gel column, eluent: dichloromethane:methanol:triethylamine = 93:6:1 by volume) to obtain the product H-3 as a light yellow oil in an 87% yield. The specific reaction formula is as follows:

[0045] The H-3 hydrogen spectrum of the ionizable lipid compound is shown in Figure 3.

[0046] Example 4 Synthesis of ionizable lipid compounds:

[0047] To a 50 mL reaction flask equipped with a magnetic separator, 10 mmol of 3,6,9,12-tetraoxatetradecane-1,14-diamine, 50 mmol of 1,2-epoxyhexadecane, and 30 mL of dichloromethane were added sequentially. The reaction tube was heated and stirred at 95°C for 84 hours. After completion of the reaction as monitored by TLC, the reaction mixture was cooled to room temperature and the solvent was removed using a rotary evaporator. The product was separated by thin-layer chromatography (silica gel column, eluent: dichloromethane:methanol:triethylamine (volume ratio = 93:6:1)) to obtain the product H-4 as a pale yellow oil in an 84% yield. The specific reaction formula is as follows:

[0048] The H-4 hydrogen spectrum of the ionizable lipid compound is shown in Figure 4.

[0049] Example 5: Synthesis of ionizable lipid compound H-5:

[0050] To a 50 mL reaction flask equipped with a magnetic separator, 10 mmol of 3,6,9,12,15-pentaoxaheptadecane-1,17-diamine, 50 mmol of 1,2-epoxytetradecane, and 30 mL of anhydrous ethanol were added sequentially. The reaction tube was heated and stirred at 90°C for 72 hours. After completion of the reaction as monitored by TLC, the reaction mixture was cooled to room temperature and the solvent was removed using a rotary evaporator. The product was separated by thin-layer chromatography (silica gel column, eluent: dichloromethane:methanol:triethylamine = 93:6:1 by volume) to obtain the milky white oily product H-5 in an 88% yield. The specific reaction formula is as follows:

[0051] The H-5 hydrogen spectrum of the ionizable lipid compound is shown in Figure 5.

[0052] Example 6:

[0053] Synthesis of Compound H-6: 10 mmol of 3,6,9,12,15-pentaoxaheptadecane-1,17-diamine, 50 mmol of 1,2-epoxyhexadecane, and 30 mL of anhydrous ethanol were added sequentially to a 50 mL reaction flask equipped with a magnetic separator. The reaction tube was heated and stirred at 90°C for 72 hours. After completion of the reaction as monitored by TLC, the reaction mixture was cooled to room temperature and the solvent was removed using a rotary evaporator. The product was separated by thin-layer chromatography (silica gel column, eluent: dichloromethane:methanol:triethylamine = 93:6:1, by volume) to obtain the milky white oily product H-6 in an 84% yield. The specific reaction formula is as follows:

[0054] The H-6 hydrogen spectrum of the ionizable lipid compound is shown in Figure 6.

[0055] Example 7 Synthesis of ionizable lipid compound H-7

[0056] To a 50 mL reaction flask equipped with a magnetic separator, 10 mmol of 3,6,9,12,15,18-hexaoxaeosane-1,20-diamine, 50 mmol of 1,2-epoxytetradecane, and 30 mL of anhydrous ethanol were added sequentially. The reaction tube was heated and stirred at 90°C for 72 hours. After completion of the reaction as monitored by TLC, the reaction mixture was cooled to room temperature and the solvent was removed using a rotary evaporator. The product was separated by thin-layer chromatography (silica gel column, eluent: dichloromethane:methanol:triethylamine = 93:6:1 by volume) to obtain the milky white oily product H-7 in an 86% yield. The specific reaction formula is as follows:

[0057] The H-7 hydrogen spectrum of the ionizable lipid compound is shown in Figure 7.

[0058] Example 8 Synthesis of ionizable lipid compound H-8:

[0059] To a 50 mL reaction flask equipped with a magnetic separator, 10 mmol of 3,6,9,12,15,18-hexaoxaescocan-1,20-diamine, 50 mmol of 1,2-epoxyhexadecane, and 30 mL of anhydrous ethanol were added sequentially. The reaction tube was heated and stirred at 90°C for 72 hours. After completion of the reaction as monitored by TLC, the reaction mixture was cooled to room temperature and the solvent was removed using a rotary evaporator. The product was separated by thin-layer chromatography (silica gel column, eluent: dichloromethane:methanol:triethylamine = 93:6:1 by volume) to obtain the milky white oily product H-8 in an 83% yield. The specific reaction formula is as follows:

[0060] The H-8 hydrogen spectrum of the ionizable lipid compound is shown in Figure 8.

[0061] Example 9 Synthesis of ionizable lipid compound H-9:

[0062] To a 50 mL reaction flask equipped with a magnetic separator, 10 mmol of 3,6,9,12,15,18,21-heptaoxatotricosane-1,23-diamine, 50 mmol of 1,2-epoxytetradecane, and 30 mL of anhydrous ethanol were added sequentially. The reaction tube was heated and stirred at 90°C for 72 hours. After completion of the reaction as monitored by TLC, the reaction mixture was cooled to room temperature and the solvent was removed using a rotary evaporator. The product was separated by thin-layer chromatography (silica gel column, eluent: dichloromethane:methanol:triethylamine = 93:6:1 by volume) to obtain the milky white oily product H-9 in an 86% yield. The specific reaction formula is as follows:

[0063] The H-9 hydrogen spectrum of the ionizable lipid compound is shown in Figure 9.

[0064] Example 10 Synthesis of ionizable lipid compound H-10:

[0065] To a 50 mL reaction flask equipped with a magnetic separator, 10 mmol of 3,6,9,12,15,18,21-heptaoxatotricosane-1,23-diamine, 50 mmol of 1,2-epoxyhexadecane, and 30 mL of anhydrous ethanol were added sequentially. The reaction tube was heated and stirred at 90°C for 72 hours. After completion of the reaction as monitored by TLC, the reaction mixture was cooled to room temperature and the solvent was removed using a rotary evaporator. The product was separated by thin-layer chromatography (silica gel column, eluent: dichloromethane:methanol:triethylamine = 93:6:1 by volume) to obtain the product H-10 as a milky white oil in an 82% yield. The specific reaction formula is as follows:

[0066] The H-10 hydrogen spectrum of the ionizable lipid compound is shown in Figure 10.

[0067] Example 11: Preparation and detection of nanolipid particles (LNP preparations)

[0068] S1. Prepare a 5 mM pH 3.0 citric acid buffer solution containing firefly luciferase (fluc) mRNA as the aqueous phase.

[0069] S2. Anhydrous ethanol solutions of the ionizable lipid compound lipids, cholesterol, and the phospholipid polyethylene glycol derivative DMG-PEG 2000 of Examples 1-10 were prepared as stock solutions at concentrations of 10 mg / ml, 10 mg / ml, and 2 mg / ml, respectively. A lipid mixed solution was prepared at a molar ratio of ionizable lipid compound lipid: cholesterol: DMG-PEG 2000 of 50:38.5:1.5 to serve as the organic phase.

[0070] S3, through the microfluidic device, the above two solutions are mixed in the microfluidic chip, the aqueous phase and organic phase solutions enter from the two sides and the middle flow path of the microfluidic chip respectively, the total flow rate of the aqueous phase is controlled at 3ml / min, the organic phase flow rate is controlled at 1ml / min, the aqueous phase: organic phase flow rate ratio is 3:1, the two phase flow paths converge in the chip and then mix, the weight ratio of total lipids to mRNA is about 15-30:1, and mRNA lipid nanoparticles (mRNA-LNP) are prepared by combining positively charged lipids with negatively charged mRNA.

[0071] In step S4, the obtained mRNA-LNPs were diluted 10-fold with 10 mM PBS buffer (pH 7.0) and purified by ultrafiltration through a 100 kDa pore size ultrafiltration tube. The ultrafiltration method was to concentrate the mRNA to 1 / 10 of its volume using a 30-degree fixed-angle rotor, a centrifugal force of 2000 g, and room temperature at 25°C.

[0072] S5, mRNA-LNP was filtered through a 0.22 μm filter membrane and stored at 2-8 °C.

[0073] S6. The average particle size and polydispersity index (PDI) of the mRNA-LNP sample were determined using a dynamic light scattering nanoparticle size analyzer. The test results are shown in Table 1.

[0074] S7. Determine the encapsulation efficiency of lipid nanoparticles using the Quant-it Ribogreen RNA Quantification Assay Kit (Thermo Fisher Scientific, UK) according to the manufacturer's instructions. Specific steps are as follows:

[0075] (1) Dilute the prepared mRNA-LNP suspension and PBS (negative control, equal volume of TE buffer) to 4 ng / μl using the TE buffer in the kit to obtain the mRNA-LNP working solution.

[0076] (2) The mRNA-LNP working solution was further diluted with TE buffer (or TE buffer containing 2% Triton-X100) to an equal volume, mixed and allowed to stand at 37°C for 10 min (TE buffer without Triton-X100 was used to determine the unencapsulated free mRNA, while TE buffer containing 2% Triton-X100 was used to determine the total mRNA in the mRNA-LNP working solution, which included free mRNA and mRNA encapsulated in lipid nanoparticles).

[0077] (3) After calibrating the fluorescence intensity: concentration standard curve with the standard, pipette an appropriate amount of Quant-it according to the kit instructions. TMRiboGreen RNA reagent nucleic acid dye was added to each group of samples and stained for 5 minutes. Each group of stained samples was transferred to a microplate reader for detection, and the mRNA in the sample was accurately quantified using software.

[0078] (4) The mRNA encapsulation efficiency in lipid nanoparticles was calculated using the following formula:

[0079] Encapsulation efficiency = [1-m(free mRNA):m(total mRNA)]×100%]. The test results are shown in Table 1.

[0080] S8, using the same preparation method, used commercial lipid SM-102 as control group 1, and prepared LNP according to the four-component formula of Moderna's new crown vaccine, that is, the molar ratio of SM102: DSPC: cholesterol: phospholipid polyethylene glycol derivative DMG-PEG 2000 was 50:10:38.5:1.5.

[0081] S9, using the same preparation method, commercial lipid SM-102 was used as control group 2 to prepare LNPs according to the three-component formula without phospholipids, that is, the molar ratio of SM102: cholesterol: phospholipid polyethylene glycol derivative DMG-PEG 2000 was 50:38.5:1.5.

[0082] Table 1

[0083] Example 12 Verification of the delivery system effect through animal in vivo experiments

[0084] mRNA lipid nanoparticles No. 1-10 prepared in Example 11 and a control sample were simultaneously injected into the leg muscles of mice at a dose of 5 μg mRNA per mouse. Twenty-four hours later, animal imaging equipment was used to measure the delivery efficacy by taking photos and calculating the fluorescence intensity at the injection site. The results are shown in Table 2 and Figure 11.

[0085] Table 2

[0086] Example 13 Accelerated stability test at 40°C

[0087] mRNA lipid nanoparticles No. 1-10 prepared in Example 11 and a control sample mRNA lipid nanoparticle were placed in a drug stability test chamber set at 40°C and 75% humidity for one month. The mRNA-LNP samples were then removed after 1 month. The average particle size and polydispersity index (PDI) were determined using a dynamic light scattering nanoparticle size analyzer, and the encapsulation efficiency of the lipid nanoparticles was determined using the Quant-it Ribogreen RNA Quantification Kit (ThermoFisher Scientific, UK). The results are shown in Table 3.

[0088] Table 3

[0089] Example 14 In vivo animal safety experiment

[0090] The mRNA lipid nanoparticles No. 1-10 prepared in Example 11 and the control sample mRNA lipid nanoparticles were simultaneously injected into the tail vein of mice at a dose of 20 μg mRNA / mouse. The clinical manifestations of the mice were observed. Physiological saline and preparation buffer (PBS) were used as controls. The results are shown in Table 4.

[0091] Table 4

[0092] It can be seen from Examples 11-14 that the compounds of the present invention have the following advantages:

[0093] 1. The three-component formula used to prepare mRNA-LNP is simpler and less expensive than the four-component formula of Moderna's SM-102 dosage form of the new crown vaccine. It is easy to scale up production and is not limited by the four-component formula range of patent No. US8058069 under the name of Arbutus.

[0094] 2 According to the data in Table 2, the in vivo delivery efficacy of mRAN-LNPs prepared from compounds H1 and H2 is comparable to that of Moderna's SM-102 ionizable lipid compound, consisting of four- and three-component LNPs. Compounds H3 and H4 exhibited delivery efficacy exceeding that of SM-102. Compounds H5-H10 exhibited an order of magnitude advantage in delivery efficacy over SM-102.

[0095] The data in Table 3 show that the three-component mRNA-LNPs prepared using compounds H1 to H10 exhibit excellent physical and chemical properties. Accelerated stability testing at 40°C for one month revealed a slight increase in particle size, while maintaining the overall structure. mRNA was well encapsulated within the LNPs without leakage. After one month at 40°C, the overall encapsulation efficiency of LNPs prepared with compounds H1-H10 was superior to that of LNPs prepared with SM-102.

[0096] Conventional mRNA vaccines are administered intramuscularly, while some cutting-edge applications, such as tumor immunomodulatory therapy, require intravenous administration of mRNA-LNPs, posing a safety challenge. The data in Table 4 demonstrate that the three-component mRNA-LNP formulations prepared with compounds H1 to H10 of the present invention exhibit a high safety profile. Following high-dose intravenous injection (20 μg mRNA / mouse via tail vein injection, equivalent to 100 μg / kg for humans, calculated based on a table in Professor Xu Shuyun's book "Pharmacological Experimental Methodology" regarding equivalent dose ratios between humans and animals based on body surface area), this dose is significantly greater than the 100 μg / person dose used in COVID-19 vaccines and sufficient to cover the maximum clinical dose), mice receiving compounds H1-H8 experienced no noticeable discomfort, while mice receiving compounds H9 and H10 experienced rapid relief of discomfort. However, mice receiving the control group, SM-102, in its three- and four-component formulations, died. This demonstrates the superior safety of the ionizable lipid compounds and corresponding LNP formulations of the present invention, far superior to that of the SM-102 compound.

Claims

1. An ionizable lipid compound, the structure of which is shown in formula (I): in, m is a positive integer selected from 3-7; R1, R2, R3, and R4 groups are each independently -H or -OH; R5, R6, R7, and R8 groups are each independently a straight chain or branched C8-20 alkyl, a straight chain or branched C8-20 alkenyl, or a straight chain or branched C8-20 alkynyl, or at least one C atom of the alkyl, alkenyl, or alkynyl group is optionally replaced by a heteroatom independently selected from O, S, or N.

2. The ionizable lipid compound according to claim 1, characterized in that m is a positive integer selected from 3-7; R1, R2, R3, and R4 groups are each independently -OH; R5, R6, R7, and R8 groups are each independently a straight chain C12-C14 alkyl group.

3. The ionizable lipid compound according to claim 2, characterized in that The R5, R6, R7, and R8 groups are each independently a straight chain C12, C13, or C14 alkyl group.

4. The ionizable lipid compound according to claim 1, characterized in that m is 3, 4, 5, 6, or 7; R1, R2, R3, and R4 groups are each independently -OH; R5, R6, R7, and R8 groups are each independently straight-chain C12, C13, or C14 alkyl groups.

5. An ionizable lipid compound selected from any one of the following compounds:

6. The ionizable lipid compound according to claim 5, characterized in that Choose from any of the following:

7. Use of the ionizable lipid compound according to any one of claims 1 to 6 in the preparation of nanolipid preparations.

8. A nano lipid particle composition, characterized in that Containing the ionizable lipid compound according to any one of claims 1 to 6.

9. The nano lipid particle composition according to claim 8, characterized in that It also contains one or more of ionizable substances, neutral lipids, and phospholipid polyethylene glycol derivatives.

10. The nano lipid particle composition according to claim 8, characterized in that The neutral lipid is selected from any one or two of DOPE and cholesterol.

11. The nano lipid particle composition according to claim 8, characterized in that The phospholipid polyethylene glycol derivative is selected from the phospholipid polyethylene glycol derivative DMG-PEG 2000.

12. The nano lipid particle composition according to claim 8, characterized in that The nano lipid particle composition is composed of the ionizable lipid compound described in any one of claims 1 to 6, cholesterol and a phospholipid polyethylene glycol derivative DMG-PEG 2000.

13. Use of the nano lipid particle composition according to claim 8 in the preparation of mRNA drugs or vaccines.

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