Application of bionic high-density lipoprotein nanoparticles in preparation of drugs targeting hepatitis A virus receptor-1

Abstract

The invention relates to the field of biological medicine, and discloses application of bionic high-density lipoprotein nanoparticles in preparation of drugs for targeting hepatitis virus receptor-1. The bionic high-density lipoprotein nanoparticle disclosed by the invention is composed of phospholipid and apolipoprotein mimetic peptide, wherein the apolipoprotein mimetic peptide is ApoA-I mimetic peptide. According to the invention, the bionic high-density lipoprotein nanoparticles can target hepatitis A virus receptor-1 for the first time, and can deliver drugs to cells of high-expression hepatitis A virus receptor-1 to play a therapeutic role. The biomimetic high-density lipoprotein nanoparticles co-loaded with anti-inflammatory and anti-fibrosis drugs can deliver the drugs to damaged renal tubules in a targeted manner especially for damaged renal tubule epithelial cells with selective high expression of KIM-1, so that kidney injuries are effectively relieved, chronic kidney diseases are treated, disease progression is relieved, and a new solution is provided for treatment of the chronic kidney diseases.

Description

Technical Field

[0001] The invention relates to the field of biopharmaceuticals, and in particular to the application of biomimetic high-density lipoprotein nanoparticles in the preparation of drugs targeting hepatitis A virus receptor-1 receptors. Background Art

[0002] Chronic kidney disease (CKD) is a chronic kidney structural and functional disorder caused by various reasons. With the increasing incidence, CKD has become one of the important public health issues, seriously threatening human health and bringing huge economic burden. How to effectively delay the progression of CKD and reduce the incidence of end-stage renal disease has always been a challenge and problem faced by the medical community. Renal fibrosis is the common pathway and main pathological basis for chronic kidney disease caused by various reasons to progress to end-stage renal failure. If it is not well controlled, fibrosis persists and eventually develops into end-stage renal disease. Patients can only rely on dialysis or even kidney transplantation, which causes a huge economic burden. At present, there is no specific drug for the treatment of CKD in clinical practice.

[0003] At present, TGFβ antibodies, angiotensin-converting enzyme inhibitors (such as captopril), kinase inhibitors, glucocorticoids, cytotoxic drugs and triptolide are commonly used in clinical practice to improve kidney function and delay the progression of the disease. However, these drugs have some limitations, often requiring large doses, no specific distribution in the kidneys, and many adverse reactions. For example, triptolide has a wide range of effects and high activity, and is a very potential anti-inflammatory and anti-fibrotic drug, but it has poor water solubility, a narrow therapeutic window, no tissue selectivity in the body, and serious toxic side effects, which greatly limits its use in clinical practice.

[0004] Constructing a kidney-targeted delivery system, selectively delivering drugs to the disease site, and reducing their distribution in other tissues and organs is of great significance for enhancing the therapeutic effect and reducing toxic side effects. Renal tubular epithelial cells are the key site of kidney damage. Even if they are victims of damage, they are also drivers of damage. As key cells in the formation of renal inflammation and fibrosis, renal tubular epithelial cells are often used as key targets for the treatment of kidney diseases. However, due to the unique physiological and pathological structure of the kidney, such as the presence of the glomerular filtration barrier, targeted delivery of renal tubular epithelial cells is difficult.

[0005] Hepatitis A virus receptor-1, also known as Kidney injury molecule-1 (KIM-1), T cell immunoglobulin mucin domain, etc., is a type 1 transmembrane protein caused by ischemia and toxic injury. KIM-1 is a functional phosphorylated serine receptor that binds and mediates the uptake of apoptotic cell bodies and is significantly upregulated in injured renal proximal tubules. Therefore, KIM-1 is of great significance in renal tubular epithelial cell injury (PTC injury) and the progression of chronic kidney disease, and can be used as a therapeutic target or a vector target.

[0006] Biomimetic high-density lipoprotein nanoparticles are mainly composed of phospholipids and apolipoproteins. They are nanoparticles that simulate endogenous high-density lipoprotein and are also an ideal delivery carrier with the advantages of small particle size, good biocompatibility, high safety, and convenient preparation. At present, because of its specific targeting of scavenger receptor B-1 (SRB-1 receptor), it is often used for tumor targeting, lymph node targeting, and liver targeting.

[0007] In summary, there is currently a severe shortage of drugs for the treatment of chronic kidney disease, and there are problems such as low drug targeting, low bioavailability, and strong toxic side effects. There is an urgent need to develop a chronic kidney disease treatment plan with high targeted delivery efficiency, convenient preparation, and good efficacy. Summary of the invention

[0008] The purpose of the present invention is to provide a new use of bionic high-density lipoprotein nanoparticles, specifically to use the bionic high-density lipoprotein nanoparticles in the preparation of drugs targeting hepatitis A virus receptor-1. As an example, using bionic high-density lipoprotein nanoparticles to co-deliver anti-inflammatory drugs and anti-fibrotic drugs to damaged renal tubular epithelial cells with high expression of KIM-1 can effectively reduce kidney damage, reduce renal fibrosis, and delay the progression of chronic kidney disease.

[0009] In order to achieve the above-mentioned invention object, the technical solution provided by the present invention is as follows:

[0010] The present invention provides an application of a bionic high-density lipoprotein nanoparticle in the preparation of a drug targeting hepatitis A virus receptor-1; the bionic high-density lipoprotein nanoparticle is composed of phospholipids and apolipoprotein mimetic peptide; the apolipoprotein mimetic peptide is an ApoA-I mimetic peptide.

[0011] Furthermore, the mass ratio of the apolipoprotein mimetic peptide to the phospholipid is 1:(2-4), preferably 1:2.

[0012] Furthermore, the sequence of the ApoA-I mimetic peptide is shown in SEQ ID NO.1, and the sequence is DWFKAFYDKVAEKFKEAF, more specifically, Ac-DWFKAFYDKVAEKFKEAF-NH2.

[0013] Furthermore, the phospholipid is one or more of dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, lecithin, 1,2-dioleoylphosphatidylcholine, and hydrogenated soybean phosphatidylcholine, preferably dimyristoylphosphatidylcholine.

[0014] Furthermore, the above-mentioned drug targeting hepatitis A virus receptor-1 is a drug that uses the bionic high-density lipoprotein nanoparticles as a carrier to encapsulate active ingredients.

[0015] Furthermore, the above-mentioned active ingredients are anti-inflammatory, anti-fibrotic and / or gene-based active ingredients, the anti-inflammatory active ingredients are one or more of glucocorticoids, triptolide, celastrol, curcumin, methotrexate, and tacrolimus, the anti-fibrotic active ingredients are one or more of nintedanib, pirfenidone, and imatinib; the gene-based active ingredients are antisense oligonucleotides or siRNA; preferably, the active ingredients are triptolide and nintedanib.

[0016] Furthermore, the above-mentioned drug targeting hepatitis A virus receptor-1 is a drug targeting cells that highly express KIM-1, TIM-1, CD365 or HAVCR-1; preferably, the cells are damaged renal tubular epithelial cells, T cells or B cells.

[0017] Furthermore, the above-mentioned drug targeting hepatitis A virus receptor-1 is a drug for treating chronic kidney disease; preferably, it is a drug for delaying the progression of chronic kidney disease, and more preferably, it is a drug for reducing kidney damage and / or reducing kidney fibrosis.

[0018] The present invention also provides a bionic high-density lipoprotein nanoparticle, which is composed of phospholipids and apolipoprotein mimicking peptides. The apolipoprotein mimicking peptide is an ApoA-I mimicking peptide, and the sequence is shown in SEQ ID NO.1.

[0019] Furthermore, the mass ratio of the apolipoprotein mimetic peptide to the phospholipid is 1:(2-4), preferably 1:2.

[0020] Furthermore, the particle size of the above-mentioned bionic high-density lipoprotein nanoparticles is 15nm to 35nm.

[0021] Beneficial effects of the present invention: The present invention proposes for the first time a scheme for using bionic high-density lipoprotein nanoparticles to deliver drugs to cells that highly express hepatitis A virus receptor-1 (including KIM-1, TIM-1, CD365 or HAVCR-1, etc.) for disease treatment, especially using bionic high-density lipoprotein nanoparticles to co-load anti-inflammatory and anti-fibrotic drugs into damaged renal tubules for the treatment of chronic kidney disease. The technical solution provided by the present invention solves the problem of lack of effective drugs for the treatment of chronic kidney disease, and also solves the problem of difficulty in targeting renal tubular epithelial cells. The bionic high-density lipoprotein nanoparticles involved in the present invention have the advantages of good targeting effect, simple preparation and high safety, and have great research value and clinical application scenarios. The use of bionic high-density lipoprotein nanoparticles to deliver the anti-inflammatory drug triptolide can not only improve its efficacy in alleviating the progression of chronic kidney disease, but also significantly reduce the toxicity of triptolide and improve its therapeutic window. As a carrier with high biocompatibility, bionic high-density lipoprotein nanoparticles can also carry other drugs to target other cells with high expression of hepatitis A virus receptor-1 for the treatment of related diseases.

[0022] Explanation of terms in this invention:

[0023] ApoA-I mimetic peptides: peptides that mimic the functions of ApoA-I, especially those that can form α-helices.

[0024] Hepatitis A virus receptor-1: A protein receptor expressed by the HAVCR1 gene (hepatitis A virus cellular receptor 1 Gene). Its name may be different when expressed in different cells, for example: kidney injury molecule-1 (KIM-1), T cell immunoglobulin domain, mucin domain protein-1 (TIM-1), etc.

[0025] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0026] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is a graph showing the expression of KIM-1 in kidney tissues of various chronic kidney disease model mice and normal mice.

[0028] Figure 2This is a semi-quantitative graph of KIM-1 protein expression in kidney tissues of various chronic kidney disease model mice and normal mice in the WB experiment.

[0029] Figure 3 This is a graph showing the expression of Havcr1 gene in kidney tissues of various chronic kidney disease model mice and normal mice.

[0030] Figure 4 The distribution of each preparation in various organs of UUO model mice 2 hours after intravenous injection.

[0031] Figure 5 This is the distribution of DiD-bHDL in the kidneys of UUO model mice 2 hours after intravenous injection.

[0032] Figure 6 This is a comparison of the distribution of DiD-bHDL in the kidneys of UUO model mice and healthy mice at different time points after intravenous injection.

[0033] Figure 7 This is a comparison chart of DiD-bHDL uptake by HK-2 cells and cisplatin-induced damaged HK-2 cells (CDDP-induced HK-2Cell).

[0034] Figure 8 The expression of KIM-1 and SRB-1 in normal and cisplatin-induced HK-2 cells.

[0035] Fig. 9 Figure 3 is the uptake of DiD-bHDL by cells before and after pretreatment of HK-2 cells with cisplatin-induced damage by KIM-1 antibody.

[0036] Fig.10 This is a comparison of the uptake of DiD-bHDL by HK-2 cells and KIM-1 overexpressing HK-2 cells.

[0037] Fig.11 This is a semi-quantitative analysis of the co-localization of KIM-1 protein with DiD-bHDL and DiD-liposome in the kidney tissue of UUO model mice.

[0038] Fig.12 This is a graph showing kidney injury scores in UUO model mice treated with different drugs.

[0039] Fig.13 This is a statistical chart of renal fibrosis area in UUO model mice treated with different drugs. DETAILED DESCRIPTION

[0040] The raw materials and equipment used in the embodiments of the present invention are all known products and can be obtained by purchasing commercially available products.

[0041] The inventors screened the types and ratios of phospholipids and apolipoprotein mimetic peptides in the early experiments and found that dimyristoylphosphatidylcholine (DMPC) was the best phospholipid. At the same time, nanoparticles with the best particle size can be obtained when the mass ratio of phospholipids and apolipoprotein mimetic peptides (peptide with the sequence DWFKAFYDKVAEKFKEAF (SEQ ID NO.1), hereinafter referred to as "4F peptide") is 2:1. The following experiments are all based on the most preferred types and ratios of nanoparticles as examples.

[0042] Example 1. Preparation of biomimetic high-density lipoprotein nanoparticles (bHDL)

[0043] 10 mg DMPC was dissolved in chloroform, and the organic solvent was removed by rotary evaporation at 37°C to form a film, and then PBS solution was added for hydration, and then an aqueous solution containing 5 mg 4F peptide was added, and ultrasonic mixing was performed to obtain the obtained biomimetic high-density lipoprotein nanoparticles. TEM observation showed that the particle size of the obtained biomimetic high-density lipoprotein nanoparticles was 15-35 nm.

[0044] Example 2: Preparation of triptolide-loaded biomimetic high-density lipoprotein nanoparticles (TP-bHDL)

[0045] 10 mg DMPC and 0.2 mg tripterygium wilfordii (TP) A were dissolved in chloroform, and the organic solvent was removed by rotary evaporation at 37°C to form a film. PBS solution was added for hydration, and then an aqueous solution containing 5 mg 4F peptide was added and ultrasonically mixed to obtain the film.

[0046] Example 3. Preparation of biomimetic high-density lipoprotein nanoparticles (BIBF-bHDL) loaded with nintedanib

[0047] 10 mg DMPC and 2 mg nintedanib (BIBF) were dissolved in chloroform, and the organic solvent was removed by rotary evaporation at 37°C to form a film. PBS solution was added for hydration, and then an aqueous solution containing 5 mg 4F peptide was added and ultrasonically mixed to obtain the film.

[0048] Example 4. Preparation of biomimetic high-density lipoprotein nanoparticles co-loaded with triptolide and nintedanib (TP / BIBF-bHDL)

[0049] 10 mg DMPC, 0.2 mg triptolide (TP) and 2 mg nintedanib (BIBF) were dissolved in chloroform, and the organic solvent was removed by rotary evaporation at 37°C to form a film. PBS solution was added for hydration, and then an aqueous solution containing 5 mg 4F peptide was added and ultrasonically mixed to obtain the film.

[0050] Comparative Example 1, Preparation of DMPC Liposome Nanoparticles

[0051] 16 mg DMPC and 2 mg cholesterol were dissolved in chloroform, and the organic solvent was removed by rotary evaporation at 37°C to form a film, which was then hydrated by adding PBS solution and subjected to ultrasonic treatment to obtain the liposome (cholesterol only plays a role in stabilizing the liposome).

[0052] The beneficial effects of the present invention are demonstrated by experimental examples below.

[0053] Experimental Example 1: Expression of KIM-1 in damaged renal tubular epithelial cells

[0054] Healthy male Balb / C mice were used to construct ureteral ligation model mice (UUO model), folic acid induced nephropathy model mice (Folic acid model) and adenine induced nephropathy model mice (Adenine model, abbreviated as ADE model) (all modeled according to conventional experimental methods of those skilled in the art). The kidneys of each nephropathy model mouse and the kidneys of normal healthy mice (Normal group, i.e. Control group) as controls were taken, and the KIM-1 protein was labeled by immunofluorescence to observe its expression. At the same time, protein blotting (WB) and RT-qPCR were used to detect the protein and gene expression levels of KIM-1 on damaged renal tubular epithelial cells.

[0055] The experimental results are as follows Figure 1 As shown, KIM-1 protein was highly expressed in the kidneys of each model mouse, and was highly co-localized with renal tubular epithelial cells marked by LTL.

[0056] like Figure 2 As shown, WB results showed that the expression of KIM-1 in the kidneys of each model mouse was significantly increased.

[0057] like Figure 3 As shown, qPCR results showed that the expression of Havcr1 gene in the kidneys of various model mice was significantly increased.

[0058] The above results indicate that KIM-1 is highly expressed in damaged renal tubular epithelial cells.

[0059] Experimental Example 2: Targeting of biomimetic high-density lipoprotein nanoparticles to damaged kidneys

[0060] Ureteral ligation model mice (UUO model) were constructed using healthy male Balb / C mice, and the distribution experiment was performed using them. In order to mark the distribution of bionic high-density lipoprotein nanoparticles in vivo, nanoparticles of Example 1 loaded with dye DiD (DiD-bHDL) were prepared, and liposome nanoparticles of Comparative Example 1 loaded with dye DiD (DiD-liposome) and free DiD were used as controls. 2 hours after tail vein injection, various tissues and organs were dissected out and placed in a living imaging instrument to observe the fluorescence distribution and perform semi-quantitative analysis. The results are shown in Figure 2. Figure 4 As shown, compared with free DiD and DiD-liposome, the distribution of DiD-bHDL in the kidney was significantly increased compared with other organs.

[0061] Furthermore, the kidneys were frozen and sectioned for immunofluorescence staining to investigate the distribution of nanoparticles in the kidneys. The experimental results are as follows: Figure 5 As shown, DiD-bHDL is more distributed in tubular epithelial cells (LTL marker) than in glomerular cells.

[0062] In addition, the distribution of DiD-bHDL in the kidneys of healthy mice and UUO model mice was compared. Figure 6 As shown, DiD-bHDL was more distributed in the damaged kidneys of UUO model mice.

[0063] Experimental Example 3: Targeting of biomimetic high-density lipoprotein nanoparticles KIM-1

[0064] The uptake of DiD-bHDL in normal HK-2 cells and cisplatin-induced HK-2 cells (i.e., damaged renal tubular epithelial cells) was compared. Figure 7 As shown in the figure, the uptake of DiD-bHDL by cisplatin-induced HK-2 cells (CDDP-induced HK-2Cell) was significantly increased; and it was found that KIM-1 expression was upregulated and SRB-1 receptor expression was downregulated in cisplatin-induced HK-2 cells ( Figure 8 ).

[0065] To prove that biomimetic high-density lipoprotein nanoparticles enter renal tubular epithelial cells through KIM-1-mediated endocytosis, competitive inhibition experiments were performed on cisplatin-induced HK-2 cells to investigate whether KIM-1 antibodies affect the ability of cisplatin-induced HK-2 cells to take up DiD-bHDL. Fig. 9As shown in the figure, after KIM-1 antibody pretreated cells, the relative fluorescence intensity in the cells was significantly reduced compared with the untreated cell control group (Control), indicating that the ability of cells to take up DiD-bHDL was significantly reduced. Fig.10 As shown, after HK-2 cells were treated with KIM-1 overexpression, the fluorescence intensity in the cells of the overexpression treatment group (OE-KIM-1HK2) increased significantly, indicating that the ability of cells to absorb DiD-bHDL increased significantly. The above results show that the higher the expression of KIM-1 in HK-2 cells, the more bionic high-density lipoprotein nanoparticles they take in, and vice versa, the less they take in, that is, the bionic high-density lipoprotein nanoparticles of the present invention target KIM-1 to play a role.

[0066] Using the liposome nanoparticles (DiD-liposome) of comparative example 1 loaded with dye DiD as a control, the co-localization of DiD-liposome and DiD-bHDL with KIM-1 was investigated by immunofluorescence co-localization experiment, and quantitative analysis was performed by Pearson coefficient. Fig.11 As shown, compared with DiD-liposome, DiD-bHDL and KIM-1 have stronger co-localization (Pearson coefficient is closer to 1), which proves that the 4F peptide in the bionic high-density lipoprotein nanoparticles of the present invention plays an important role in targeting KIM-1.

[0067] Experimental Example 4: Study on the efficacy of biomimetic high-density lipoprotein nanoparticles co-loaded with triptolide (TP) and nintedanib (BIBF) in the treatment of chronic kidney disease

[0068] Using Example 4 as an example to test the drug, a UUO model mouse was constructed to investigate the therapeutic effect of the bionic high-density lipoprotein nanoparticles of the present invention as a carrier for drug loading on chronic kidney disease. The specific method is as follows:

[0069] According to the principle of random grouping, sham-operated mice and UUO model mice were randomly divided into 8 groups:

[0070] (1) Blank control group (Control) (n=5): sham-operated mice were injected with PBS solution through the tail vein every two days for 14 consecutive days;

[0071] (2) PBS group (n = 5): UUO model mice were injected with PBS solution through the tail vein once every two days for 14 consecutive days;

[0072] (3) Free TP solution group (n = 5): UUO model mice were injected with TP solution (dose in terms of TP, 0.2 mg / kg) via tail vein, once every two days for 14 consecutive days;

[0073] (4) Free BIBF solution group (n = 5): UUO model mice were injected with BIBF solution (dose based on BIBF, 2 mg / kg) via tail vein, once every two days for 14 consecutive days;

[0074] (5) Free TP / BIBF mixed solution group (n=5): UUO model mice were injected with TP / BIBF mixed solution (TP 0.2 mg / kg, BIBF 2 mg / kg) through the tail vein, once every two days for 14 consecutive days;)

[0075] (6) TP-bHDL solution group (n = 5): UUO model mice were injected with TP-bHDL (dose in terms of TP, 0.2 mg / kg) via tail vein, once every two days for 14 consecutive days;

[0076] (7) BIBF-bHDL solution group (n = 5): UUO model mice were injected with BIBF-bHDL (dose based on BIBF, 2 mg / kg) via tail vein, once every two days for 14 consecutive days;

[0077] (8) TP / BIBF-bHDL group (n=5): UUO model mice were injected with TP / BIBF-bHDL (TP 0.2 mg / kg, BIBF 2 mg / kg) via tail vein, once every two days for 14 consecutive days.

[0078] After completing the treatment according to the dosage regimen, the kidney tissue was stained with HE and Masson to observe the kidney lesions and fibrosis.

[0079] In order to evaluate the degree of renal injury, this study used pathological scoring to quantitatively analyze renal lesions. Renal tissue sections were observed under an optical microscope, and the renal injury index was comprehensively evaluated based on pathological features such as degeneration and necrosis of tubular epithelial cells, tubular dilatation, protein cast formation, fibrous tissue proliferation and inflammatory cell infiltration. The score was scored using a four-level grading method, in which 0 points indicated normal tissue structure with no obvious lesions; 1 point indicated mild injury, 2 points indicated mild injury, 3 points indicated moderate injury, and 4 points indicated severe injury. The experimental results showed that the degree of renal injury in the model group mice was significantly higher than that in the control group and each drug-treated group; after intervention with different drugs, the renal injury of mice in each treatment group was alleviated, and the scores were lower than those in the model group. Among them, the TP / BIBF-bHDL treatment group had the lowest degree of injury (such as Fig.12 ), suggesting that it has the best renal protective effect.

[0080] To evaluate the degree of tissue fibrosis, the Image-Pro Plus 6.0 image analysis system (MediaCybernetics, USA) was used to measure the fibrous tissue area (Area) in the collected images, and the percentage of fibrous tissue expression area was calculated = fibrous tissue area / field of view area (pixel area). Fig.13 As shown in the figure, after treatment with different drugs, the degree of fibrosis in each treatment group was alleviated, among which the TP / BIBF-bHDL treatment group had the smallest fibrosis area, indicating that TP / BIBF-bHDL has a significant effect in alleviating renal tissue fibrosis.

[0081] In summary, the present invention proposes for the first time a scheme for using bionic high-density lipoprotein nanoparticles to deliver drugs to cells that highly express hepatitis A virus receptor-1 (including KIM-1, TIM-1, CD365 or HAVCR-1, etc.) for disease treatment, especially using bionic high-density lipoprotein nanoparticles to co-load anti-inflammatory and anti-fibrotic drugs to damaged renal tubules for the treatment of chronic kidney disease. The technical solution provided by the present invention solves the problem of lack of effective drugs for the treatment of chronic kidney disease, and also solves the problem of difficult targeting of renal tubular epithelial cells. The bionic high-density lipoprotein nanoparticles involved in the present invention have the advantages of good targeting effect, simple preparation and high safety, and have great research value and clinical application scenarios. The use of bionic high-density lipoprotein nanoparticles to deliver the anti-inflammatory drug triptolide can not only improve its efficacy in alleviating the progression of chronic kidney disease, but also significantly reduce the toxicity of triptolide and improve its therapeutic window. As a carrier with high biocompatibility, bionic high-density lipoprotein nanoparticles can also carry other drugs to target other cells with high expression of hepatitis A virus receptor-1 for the treatment of related diseases.

Claims

1. Application of bionic high-density lipoprotein nanoparticles in the preparation of drugs targeting hepatitis A virus receptor-1; the bionic high-density lipoprotein nanoparticles are composed of phospholipids and apolipoprotein mimetic peptides; the apolipoprotein mimetic peptide is an ApoA-I mimetic peptide.

2. The use according to claim 1, characterized in that: The mass ratio of the apolipoprotein mimetic peptide to phospholipid is 1:(2-4), preferably 1:

2.

3. The use according to claim 1, characterized in that: The ApoA-I mimetic peptide sequence is shown in SEQ ID NO.

1.

4. The use according to claim 1, characterized in that: The phospholipid is one or more of dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, lecithin, 1,2-dioleoylphosphatidylcholine, and hydrogenated soybean phosphatidylcholine, preferably dimyristoylphosphatidylcholine.

5. The use according to claim 1, characterized in that: The drug targeting hepatitis A virus receptor-1 is a drug that uses the bionic high-density lipoprotein nanoparticles as a carrier to encapsulate active ingredients.

6. The use according to claim 5, characterized in that: The active ingredients are anti-inflammatory, anti-fibrotic and / or gene-based active ingredients. The anti-inflammatory active ingredients are one or more of glucocorticoids, triptolide, celastrol, curcumin, methotrexate, and tacrolimus. The anti-fibrotic active ingredients are one or more of nintedanib, pirfenidone, and imatinib. The gene-based active ingredients are antisense oligonucleotides or siRNAs. Preferably, the active ingredients are triptolide and nintedanib.

7. The use according to claim 1, characterized in that: The drug targeting hepatitis A virus receptor-1 is a drug targeting cells that highly express KIM-1, TIM-1, CD365 or HAVCR-1; preferably, the cells are damaged renal tubular epithelial cells, T cells or B cells.

8. The use according to claim 1, characterized in that: The drug targeting hepatitis A virus receptor-1 is a drug for treating chronic kidney disease; preferably, it is a drug for delaying the progression of chronic kidney disease, and more preferably, it is a drug for alleviating kidney damage and / or alleviating kidney fibrosis.

9. A bionic high-density lipoprotein nanoparticle, characterized in that: It is composed of phospholipids and apolipoprotein mimicking peptides. The apolipoprotein mimicking peptide is an ApoA-I mimicking peptide, and its sequence is shown in SEQ ID NO.

1.

10. The biomimetic high-density lipoprotein nanoparticle according to claim 9, characterized in that: The mass ratio of the apolipoprotein mimetic peptide to phospholipid is 1:(2-4), preferably 1:

2.

11. The biomimetic high-density lipoprotein nanoparticle according to claim 9, characterized in that: The particle size is 15nm~35nm.

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