Fluorinated inhalable / oral liposome nanoparticle drug delivery platform and preparation and application thereof

Abstract

The invention discloses a fluorinated inhalable / oral liposome nanoparticle drug delivery platform as well as a preparation method and application thereof. The fluorinated inhalable / oral liposome nanoparticle drug delivery platform has a core-shell structure, and the core-shell structure comprises a lipid core layer and a responsive cross-linked shell layer; the lipid core layer comprises ionizable lipid containing tertiary amino, a DSPE derivative grafted with a carbon-carbon double bond structure fragment, sterol and PEGylated lipid and wraps a medicine; the responsive crosslinking shell layer is formed by performing carbon-carbon double bond polymerization on materials containing PFA and ROS responsive crosslinking agents and the DSPE derivative in the lipid core layer. According to the invention, the outer layer of LNPs is modified with a fluorinated polymer shell layer to expand the administration route of the LNPs, so that the problem that the LNPs are difficult to efficiently and orally deliver is solved.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of lipid nanoparticles (LNPs), in particular to a fluorinated inhalable / oral liposome nanoparticle drug delivery platform and its preparation method and application. BACKGROUND

[0002] The limitations of traditional LNPs mainly lie in their insufficient stability and controllable release ability. Although traditional LNPs have high drug loading capacity and good biocompatibility, in complex physiological environments (such as lung mucus or blood), they are easily destroyed by shear force or enzymatic action, leading to premature drug leakage or uncontrollable release process. Taking the case of the drug intended target site being the heart: for long-term diseases such as ischemic heart disease, inhalation or oral administration, which is non-invasive and can be operated by patients at home, is more conducive to long-term disease management; among them, inhalation administration can directly reach the heart by lung-heart circulation, with higher delivery efficiency. However, inhalation LNPs still need to overcome many challenges, including shear force during atomization process, and various lung barrier mechanisms, such as airway mucus-cilia clearance limiting drug delivery to alveoli, alveolar epithelial and capillary endothelial barrier hindering transmembrane transport, rapid clearance effect of the circulatory system affecting drug sustained action, and low target organ action efficiency of systemic administration. In addition to the above challenges, oral LNPs also face the problems of first-pass effect, gastric and intestinal acid-base environment, and degradation of LNPs by pepsin. Patent application CN202310662773.5 mentions that conventional liposomes often cause systemic side effects due to non-specific distribution in targeted delivery, and lack of intelligent release mechanism in response to disease microenvironment (such as ROS, pH).

[0003] Inhalation administration can directly deliver drugs to the lungs or systemic circulation, avoiding the first-pass effect, and is particularly suitable for local treatment of respiratory diseases (such as asthma, lung cancer) and systemic diseases. For example, the ROS-responsive liposome (RALP@HOC@Fe3O4) developed by Suzhou University can target the regulation of tumor microenvironment through inhalation delivery, enhancing the photodynamic / chemodynamic efficacy.

[0004] The challenge of inhalation administration lies in the fact that the shear force generated during aerosolization easily destroys the structure of liposomes, leading to drug leakage or carrier aggregation. In addition, the clearance mechanism of lung mucus layer and the phagocytosis of alveolar macrophages further limit the residence time and efficacy of LNPs.

[0005] Currently, the existing technology still has the following unsolved key problems: 1) Insufficient inhalation adaptability: most LNP designs do not consider the physical stability during inhalation, and lack protection mechanisms against shear force.

[0006] 2) Balance of controlled release and targeting: existing systems are difficult to achieve high drug loading, accurate controlled release and efficient targeting at the same time, for example, the mitochondria-targeting quercetin liposome of patent application CN202111084330.X improves the targeting through TPP modification, but the ROS response rate and drug release kinetics still need to be optimized.

[0007] 3) Bottleneck of large-scale production: the preparation process of liposomes with complex structure (such as multi-layer polymer modification) is complicated, which is difficult to meet the demand of large-scale production in clinic.

[0008] Most of the existing polymer-lipid nanocomposites are to connect polymer molecules to phospholipids, and then synthesize hybrid LNPs in one step, which do not contain a stable polymer shell and cannot withstand inhalation shear stress or oral barriers. For example, the patent specification with publication number CN119506361A discloses a PBAEDOPEPEG2000 polymer-lipid nanocomposite, its preparation method and application. The patent technology uses a dimethyl sulfoxide: ethanol solution mixed with DOPEPEG2000 lipids and PBAE as the oil phase, and a sodium acetate / acetic acid buffer solution as the water phase, to obtain a PBAEDOPEPEG2000 polymer-lipid nanocomposite by microfluidic synthesis. The polymer-lipid nanocomposite can efficiently load exogenous genes, change its surface properties and improve the stability of the nanoparticles by introducing DOPEPEG2000 lipids, promote membrane fusion, reduce lysosomal degradation risk, and accelerate the transfection process of exogenous genes in recipient cells, and achieve high-efficiency expression in 293FT cells.

[0009] In summary, existing LNPs cannot be administered by inhalation or oral administration, which is high in patient compliance, convenient, and low in medical cost, because existing LNPs cannot withstand the shear stress during inhalation and cannot withstand the gastrointestinal barrier during oral administration, which will lead to the collapse of the structure of LNPs and drug leakage. SUMMARY

[0010] The present application provides a fluorinated inhalable / oral liposome nanoparticle drug delivery platform, its preparation method and application. The fluorinated polymer shell is modified on the outer layer of LNPs to solve the above problems, expand the administration route of traditional LNPs, and solve the problem of difficult efficient oral delivery of LNPs. Specifically, the above technical problems are solved by the following aspects: (1) Coping with shear stress during inhalation: conventional LNPs prepared by hydrophobic and hydrophilic non-covalent interactions are prone to disintegration during inhalation. The fluorination method provided by the present application forms a protective shell on the surface of LNPs through covalent bonding, greatly improving the structural tolerance.

[0011] (2) To overcome the oral gastrointestinal barrier: the tightly cross-linked polymer shell can help LNPs maintain structural stability in acid / alkali environment.

[0012] (3) In addition to (1) and (2), both inhalation and oral administration need to overcome the mucous epithelial barrier to achieve blood entry. The hydrophobic properties of fluorinated alkanes can help LNPs overcome.

[0013] The specific technical solutions are as follows: In a first aspect, the present application provides a fluorinated inhalable / oral liposome nanoparticle drug delivery platform, which has a core-shell structure, and the core-shell structure comprises a lipid core layer and a responsive cross-linked shell layer. The lipid core layer comprises ionizable lipids containing tertiary amine groups, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) derivatives grafted with carbon-carbon double bond structure fragments, sterols, and PEGylated lipids, and is wrapped with drugs. The responsive cross-linked shell layer is formed by polymerization of materials including PFA and ROS-responsive cross-linking agents with the DSPE derivatives in the lipid core layer through carbon-carbon double bonds.

[0014] The ionizable lipids containing tertiary amine groups can include SM-102 (a commercial lipid) and the like.

[0015] The DSPE derivative grafted with carbon-carbon double bond structure fragments can include DSPE-A and the like, and DSPE-A is an amide product generated by the reaction of methacryloyl chloride and DSPE.

[0016] The sterol can include cholesterol and the like.

[0017] The PEGylated lipids can include DMG-PEG 2000 (a commercial liposome) and the like.

[0018] In a second aspect, the present application provides a preparation method of a fluorinated inhalable / oral liposome nanoparticle drug delivery platform, comprising: Mixing the DSPE derivative grafted with carbon-carbon double bond structure fragments (such as DSPE-A and the like), ionizable lipids containing tertiary amine groups (such as SM-102 and the like), sterols (such as cholesterol and the like), PEGylated lipids (such as DMG-PEG 2000 and drugs in an organic solvent, then mixing with water and adding to a microfluidic device, and blending to prepare LNPs. The obtained mixture is dialyzed in water, and then freeze-dried to obtain drug-loaded LNPs. The drug-loaded LNPs, 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctyl acrylate (PFA) and ROS (reactive oxygen species) responsive crosslinking agent are dispersed in water, an initiator is added, a crosslinking polymerization reaction is carried out, the reaction product is dialyzed to remove unreacted small molecules, and a fluorinated inhalable / oral liposome nanoparticle drug delivery platform is obtained; In the total mass of the DSPE derivative grafted with a carbon-carbon double bond structure segment, the ionizable lipid containing a tertiary amine group, the phytosterol and the PEGylated lipid is 100%, the amount of the DSPE derivative grafted with a carbon-carbon double bond structure segment is 10% to 15%, and the amount of PFA is 5% to 10%.

[0019] Further, in the total mass of the DSPE derivative grafted with a carbon-carbon double bond structure segment, the ionizable lipid containing a tertiary amine group, the phytosterol and the PEGylated lipid is 100%, the amount of the ionizable lipid containing a tertiary amine group is 45% to 50%, and the amount of the PEGylated lipid is 1% to 2%, for example, 1.5%, etc.

[0020] In the present application, the structural formula of the amide product DSPE-A can be represented as follows: .

[0021] The method for preparing the amide product DSPE-A in the present application is an acyl chloride and amine nucleophilic addition reaction well known in the art, which can be entrusted to a synthesis company for synthesis or self-made, and an exemplary specific preparation process is introduced as follows: a mixed solution of methyl acryloyl chloride (which can be excessive) and triethylamine (TEA) is added dropwise to a DSPE solution at 0-5 DEG C, the pH is kept at 8-9, the temperature is increased to room temperature (for example, 25 DEG C, etc.), and the reaction time can be 12 hours, etc., and thin layer chromatography (TLC) is monitored (developing agent: CHCl3 / MeOH / NH4OH volume ratio = 65 / 25 / 4); after the reaction is completed, the solvent is removed by rotary evaporation, and the residue is purified by a silica gel column (gradient elution: CHCl3→ CHCl3 / MeOH volume ratio 9 / 1) to obtain DSPE-A.

[0022] In the present application, the drug-loaded LNPs are coated with modifiable sites (carbon-carbon double bonds) capable of free radical polymerization on the surface, and the density of the modifiable sites (carbon-carbon double bonds) on the surface of the drug-loaded LNPs can be adjusted by adjusting the proportion of the DSPE derivative of the grafted carbon-carbon double bond structure fragment. The present application provides drug-loaded LNPs coated with modifiable sites (carbon-carbon double bonds) capable of free radical polymerization on the surface, and the key component of the drug-loaded LNPs affecting the modifiable sites (carbon-carbon double bonds) is the DSPE derivative of the grafted carbon-carbon double bond structure fragment. The more this component is added, the more the sites capable of polymer modification are, and the greater the density of the modified polymer is. The polymer density and composition can be adjusted according to different drug delivery or targeting requirements, and therefore the final fluorinated modification-LNPs can be referred to as a universal drug delivery platform.

[0023] The present application modifies a fluorinated polymer shell layer on the surface of drug-loaded LNPs by a system capable of free radical polymerization at room temperature in an aqueous phase. The fluorinated inhalable / oral liposome nanoparticle drug delivery platform of the present application is drug-loaded LNPs coated with a fluorinated polymer shell layer, which includes a core carrier (a DSPE derivative of a grafted carbon-carbon double bond structure fragment, an ionizable lipid containing a tertiary amine group, a sterol, and a PEGylated lipid), a drug (a nucleic acid drug or a chemical drug, which can be selected according to the final disease to be treated), and a modification layer (2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctyl acrylate, which is modified on the outer layer of the LNPs by free radical polymerization). The fluorinated polymer shell layer constructed by free radical crosslinking can expand the drug delivery mode of the LNPs, adjust the addition proportion of the DSPE derivative of the grafted carbon-carbon double bond structure fragment, adjust the modification density and composition of the polymer shell layer, and adapt to different drug delivery modes and purposes, from intravenous injection to inhalation and oral administration, increase patient compliance, and be suitable for long-term management (e.g., chronic heart failure). The inhalation drug delivery route can quickly reach the heart through the pulmonary-cardiac circulation, efficiently deliver drugs for treating cardiovascular diseases, and rapidly relieve symptoms (e.g., acute myocardial infarction).

[0024] Further, the preparation method of the fluorinated inhalable / oral liposome nanoparticle drug delivery platform, the drug is wrapped inside the drug-loaded LNPs, and does not react chemically with the DSPE derivative of the grafted carbon-carbon double bond structure fragment, the ionizable lipid containing a tertiary amine group, the sterol, and the PEGylated lipid. The drug can include roxadustat, etc.

[0025] The preparation method of the fluorinated inhalable / oral liposome nanoparticle drug delivery platform, based on the total mass of the DSPE derivative of the grafted carbon-carbon double bond structure fragment, the ionizable lipid containing a tertiary amine group, the sterol, and the PEGylated lipid being 100%, the amount of the drug can be 20%, etc.

[0026] The preparation method of the fluorinated inhalable / oral liposome nanoparticle drug delivery platform, the organic solvent can include one or two of ethanol, N,N-dimethylformamide (DMF) and the like.

[0027] The preparation method of the fluorinated inhalable / oral liposome nanoparticle drug delivery platform, if there is no ROS-responsive crosslinking agent, the reaction generates a linear or branched polymer, and there is no crosslinking network, and the structure is not as stable as that of the ROS-responsive crosslinking agent. The ROS-responsive crosslinking agent has an active bond in the middle, such as a disulfide bond, a diselenide bond, a ketone thio-ketal bond (TK bond), etc. N,N'-bis(acryloyl) cystamine (BAC) has an active disulfide bond in the middle, which will break under ROS response, so it has the ability of responsive degradation. In addition, the addition of the ROS-responsive crosslinking agent can also help the drug to be released in response to ROS at the lesion. The ROS-responsive crosslinking agent can include N,N'-bis(acryloyl) cystamine (BAC) and the like.

[0028] The preparation method of the fluorinated inhalable / oral liposome nanoparticle drug delivery platform, in terms of the total mass of the DSPE derivative grafted with a carbon-carbon double bond structure segment, the ionizable lipid containing a tertiary amine group, the phytosterol, and the PEGylated lipid being 100%, the amount of the ROS-responsive crosslinking agent can be 5% to 10%.

[0029] The preparation method of the fluorinated inhalable / oral liposome nanoparticle drug delivery platform, the initiator can be an ammonium persulfate-N,N,N',N'-tetramethyl ethylenediamine initiation system. Further, in terms of the total mass of the DSPE derivative grafted with a carbon-carbon double bond structure segment, the ionizable lipid containing a tertiary amine group, the phytosterol, the PEGylated lipid, the PFA, and the ROS-responsive crosslinking agent being 100%, the amount of ammonium persulfate in the ammonium persulfate-N,N,N',N'-tetramethyl ethylenediamine initiation system can be 1.5% to 2.5%, for example, 2%, and the amount of N,N,N',N'-tetramethyl ethylenediamine can be 3% to 5%, for example, 4%.

[0030] The preparation method of the fluorinated inhalable / oral liposome nanoparticle drug delivery platform, the fluorinated inhalable / oral liposome nanoparticle drug delivery platform is a spherical nanoparticle, the average particle size is 60 to 80 nm, and the average particle size after atomization is 70 to 90 nm.

[0031] The fluorinated inhalable / oral liposome nanoparticle drug delivery platform of the first aspect can be prepared by the preparation method of the fluorinated inhalable / oral liposome nanoparticle drug delivery platform of the second aspect.

[0032] In a third aspect, the present application provides the fluorinated inhalable / oral liposome nanoparticle drug delivery platform prepared by the preparation method of the second aspect.

[0033] In a fourth aspect, the present application provides the use of the fluorinated inhalable / oral liposome nanoparticle drug delivery platform of the first aspect or the fluorinated inhalable / oral liposome nanoparticle drug delivery platform prepared by the method of the second aspect or the fluorinated inhalable / oral liposome nanoparticle drug delivery platform prepared by the method of the second aspect in the preparation of an inhalable / oral drug preparation. The specific application field can be cardiovascular diseases, mainly ischemic heart disease. This long-term disease, non-invasive, patient self-operation inhalation / oral administration is more conducive to the long-term management of their condition, inhalation administration can also directly reach the heart through the pulmonary-cardiac circulation, high efficiency.

[0034] Compared with the prior art, the present application has the following beneficial effects: 1. The fluorinated polymer is used to improve the structural stability of LNPs to cope with inhalation shear force and oral gastrointestinal barrier, and the existing LNP administration method is expanded from intravenous injection to atomization inhalation and oral administration. Specifically, the present application improves the structural stability by covalently modifying the fluorinated polymer shell layer to resist inhalation shear force and oral gastrointestinal acid / alkali environment.

[0035] 2. By combining LNPs and fluorinated polymers, not only can the hydrophobicity and chemical inertness after fluorination provide a similar PEG stabilizing effect, but also can avoid the immune response caused by conventional PEG-LNPs, i.e. avoiding the production of anti-PEG IgM and anti-PEG IgG in the body, avoiding accelerated blood clearance and hypersensitivity reaction, reducing the probability of LNP clearance or premature drug release. BRIEF DESCRIPTION OF DRAWINGS

[0036] Figure 1 NMR spectrum of the amide product DSPE-A of Example 1 in CDCl3.

[0037] Figure 2 Freeze electron microscope photo of the fluorinated inhalable / oral liposome nanoparticle drug delivery platform of Example 2. DETAILED DESCRIPTION

[0038] The present application will be further described below in conjunction with the drawings and specific examples. It should be understood that these examples are only used to illustrate the present application and not to limit the scope of the present application.

[0039] Example 1: Preparation of DSPE-A: The DSPE solution was cooled to 0-5 °C in an ice bath; methyl acryloyl chloride and TEA (pre-mixed) were added dropwise slowly, keeping pH = 8-9; the temperature was raised to 25 °C for 12 hours of reaction, and TLC monitoring (developing agent: CHCl3 / MeOH / NH4OH volume ratio = 65 / 25 / 4); after the reaction was completed, the solvent was removed by rotary evaporation, and the residue was purified by a silica gel column (gradient elution: CHCl3→ CHCl3 / MeOH volume ratio 9 / 1) to obtain DSPE-A, and the results of its nuclear magnetic characterization are shown in Figure 1 .

[0040] Example 2: The final concentration of the lipid ethanol solution was 10 mg / mL, and the volume ratio of SM-102:DSPE-A:Cholesterol:DMG-PEG 2000 = 50:10:38.5:1.5 was mixed to obtain an ethanol mixed solution with a total volume of 1 mL. A 20 mg / mL Roxadustat (FG-4592) DMF solution was prepared separately, 0.1 mL of the solution was added to the obtained ethanol mixed solution, and the resulting mixed solution was mixed with water in a volume ratio of 1:4. The microfluidic device was added, and the drug-loaded LNPs were prepared by blending at a rate of 12 mL / min. The resulting mixture was dialyzed in pure water, and the drug-loaded LNPs were collected and refrigerated for use.

[0041] The obtained drug-loaded LNPs (SM-102, DSPE-A, Cholesterol and DMG-PEG 2000 with a total mass of 10 mg) were dispersed in 6 mL of water with PFA (0.5 mg) and BAC (1 mg), and ammonium persulfate (2 wt% of the total mass, 0.24 mg) and tetramethyl ethylenediamine (4 wt% of the total mass, 0.48 mg) were added to initiate the polymerization reaction, and the reaction time was 2 h. The product was dialyzed in a 1000 Da dialysis bag to remove unreacted small molecules, and the fluorinated shell-modified LNP product, i.e., the fluorinated inhalable / oral liposome nanoparticle drug delivery platform, was obtained, as shown in Figure 2 , which presented as uniformly dispersed spherical nanoparticles.

[0042] Example 3: The difference from Example 2 is only that the amount of PFA is changed to 1 mg, and the rest is the same, and the fluorinated shell-modified LNP product is obtained.

[0043] Example 4: The difference from Example 3 is only that the lipid ethanol solution is mixed according to the volume ratio of SM-102:DSPE-A:Cholesterol:DMG-PEG 2000= 45: 15: 38.5: 1.5 by volume, and the rest are the same, to obtain the fluorinated shell modified LNP product.

[0044] Example 5: The difference from Example 4 is only that the amount of PFA is changed to 1.5 mg, and the rest are the same, to obtain the fluorinated shell modified LNP product.

[0045] Example 6: The difference from Example 5 is only that the ethanol solution of lipids is mixed according to SM-102: DSPE-A: Cholesterol: DMG-PEG 2000 = 45: 20: 33.5: 1.5 by volume, and the rest are the same, to obtain the fluorinated shell modified LNP product.

[0046] Example 7: The difference from Example 3 is only that the ethanol solution of lipids is mixed according to SM-102: DSPE-A: Cholesterol: DMG-PEG 2000 = 50: 20: 28.5: 1.5 by volume, and the rest are the same, to obtain the fluorinated shell modified LNP product.

[0047] Comparative Example 1: The difference from Example 2 is only that no PFA is added, i.e. the amount of PFA is changed to 0 mg, and the rest are the same, to obtain the non-fluorinated shell modified LNP product.

[0048] Dynamic light scattering (DLS) particle size detection: 4 mg of the LNP product prepared in the examples or comparative examples was weighed and dispersed in 4 mL of PBS solution to obtain a solution with a concentration of 1 mg / mL. 1 mL of the solution was taken and added to a cuvette, and then placed into a laser particle size analyzer for testing to obtain the DLS particle size result before atomization.

[0049] The atomization stability was detected by the change of particle size after atomization. If the change of particle size is not large, it is considered to be structurally stable. 250 μL of the LNP product solution of the examples or comparative examples was loaded into an atomization high-pressure pusher, and the atomized LNP solution was collected. The DLS particle size result of the atomized LNP solution was detected to obtain the DLS particle size result after atomization.

[0050] Table 1 shows the DLS particle size detection results of the LNP products of the examples and comparative examples before and after atomization.

[0051] Table 1 As shown in Table 1, compared with the LNP without fluorinated polymer shell in Comparative Example 1, the LNP with fluorinated polymer shell in Examples 2-4 has obvious effect of resisting nebulization shear force, and the particle size is relatively stable before and after nebulization, but too high concentration of DSPE-Acrylate and PFA (e.g. Examples 5-7) may form too thick shell, resulting in increased particle size.

[0052] The high shear force generated by the nebulization device (such as compressed air or ultrasonic nebulizer) can largely destroy the structural integrity of the LNP, which may lead to the disintegration or recombination of the lipid layer, thus the particle size of the LNP without fluorinated polymer shell in Comparative Example 1 increases a lot. However, the particle size of the LNP with the tightly cross-linked fluorinated polymer shell after nebulization is greatly reduced (the average particle size of the LNP product in Examples 2-4 is still <100 nm after nebulization, which does not affect the subsequent lung deposition and blood entry).

[0053] Furthermore, it is understood that various modifications and changes can be made to the present application by those skilled in the art reading the above description of the present application, and these equivalent forms also fall within the scope defined by the claims attached hereto.

Claims

1. A fluorinated inhalable / oral liposomal nanoparticle drug delivery platform, characterized in that, The fluorinated inhalable / oral liposome nanoparticle drug delivery platform has a core-shell structure, which includes a lipid core layer and a responsive cross-linked shell layer. The lipid core layer comprises ionizable lipids containing tertiary amine groups, DSPE derivatives grafted with carbon-carbon double bond structural fragments, sterols, and PEGylated lipids, and encapsulates the drug. The responsive cross-linked shell is formed by the polymerization of materials including PFA and ROS responsive cross-linking agents with DSPE derivatives in the lipid core layer via carbon-carbon double bonds.

2. A method for preparing a fluorinated inhalable / oral liposome nanoparticle drug delivery platform, characterized in that, include: DSPE derivatives grafted with carbon-carbon double bond structural fragments, ionizable lipids containing tertiary amine groups, sterols, PEGylated lipids and drugs were mixed in an organic solvent and then mixed with water and added to a microfluidic device to prepare LNPs. The resulting mixture was dialyzed in water and lyophilized to obtain drug-loaded LNPs. Drug-loaded LNPs, PFAs, and ROS-responsive crosslinking agents were dispersed in water, and an initiator was added to carry out a crosslinking polymerization reaction. The reaction product was dialyzed to remove unreacted small molecules, resulting in a fluorinated inhalable / oral liposome nanoparticle drug delivery platform. Based on the total mass of DSPE derivatives grafted with carbon-carbon double bond structural fragments, ionizable lipids containing tertiary amine groups, sterols and PEGylated lipids as 100%, the amount of DSPE derivatives grafted with carbon-carbon double bond structural fragments is 10%~15%, and the amount of PFA is 5%~10%.

3. The preparation method according to claim 2, characterized in that, Based on the total mass of DSPE derivatives grafted with carbon-carbon double bond structural fragments, ionizable lipids containing tertiary amine groups, sterols and PEGylated lipids as 100%, the amount of ionizable lipids containing tertiary amine groups is 45%~50%, and the amount of PEGylated lipids is 1%~2%.

4. The preparation method according to claim 2, characterized in that, The drug mentioned includes roxadustat.

5. The preparation method according to claim 2, characterized in that, The organic solvent includes one or both of ethanol and DMF.

6. The preparation method according to claim 2, characterized in that, The ROS-responsive crosslinking agent includes BAC.

7. The preparation method according to claim 2 or 6, characterized in that, The amount of the ROS-responsive crosslinking agent is 5% to 10%, based on the total mass of the DSPE derivative grafted with carbon-carbon double bond structural fragments, the ionizable lipid containing tertiary amine groups, the sterol and the PEGylated lipid, which is 100%.

8. The preparation method according to claim 2, characterized in that, The initiator is an ammonium persulfate-N,N,N',N'-tetramethylethylenediamine initiation system, wherein, based on the total mass of DSPE derivatives grafted with carbon-carbon double bond structural fragments, ionizable lipids containing tertiary amine groups, sterols, PEGylated lipids, PFA, and ROS-responsive crosslinking agents as 100%, the amount of ammonium persulfate is 1.5%~2.5%, and the amount of N,N,N',N'-tetramethylethylenediamine is 3%~5%.

9. The preparation method according to claim 2, characterized in that, The fluorinated inhalable / oral liposome nanoparticle drug delivery platform consists of spherical nanoparticles with an average particle size of 60-80 nm, and an average particle size of 70-90 nm after atomization.

10. The application of the fluorinated inhalable / oral liposome nanoparticle drug delivery platform according to claim 1, or the preparation method according to any one of claims 2 to 9, or the fluorinated inhalable / oral liposome nanoparticle drug delivery platform prepared by the preparation method according to any one of claims 2 to 9, in the preparation of inhalable / oral drug formulations.

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