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

Abstract

The present invention relates to the field of biomedicine and discloses the use of a biomimetic high-density lipoprotein nanoparticle in the preparation of a drug targeting hepatitis A virus receptor 1. The biomimetic high-density lipoprotein nanoparticle of the present invention is composed of phospholipids and apolipoprotein mimetic peptides, and the apolipoprotein mimetic peptide is an ApoA-I mimetic peptide. The present invention proposes for the first time that biomimetic high-density lipoprotein nanoparticles can target hepatitis A virus receptor 1 and deliver drugs to cells that highly express hepatitis A virus receptor 1 to exert a therapeutic effect. In particular, for damaged renal tubular epithelial cells that selectively highly express KIM-1, biomimetic high-density lipoprotein nanoparticles co-loaded with anti-inflammatory and anti-fibrotic drugs can deliver drugs to damaged renal tubules in a targeted manner, effectively reducing kidney damage, treating chronic kidney disease, and alleviating disease progression, thereby providing a new solution for the treatment of chronic kidney disease.

Description

Technical Field

[0001] The present 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 structural and functional disorder of the kidneys caused by various reasons. With the increasing incidence, CKD has become one of the important public health issues, seriously threatening human health and bringing a 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 the progression of chronic kidney disease caused by various reasons 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] Currently, TGFβ antibodies, angiotensin-converting enzyme inhibitors (such as captopril), kinase inhibitors, glucocorticoids, cytotoxic drugs, and triptolide are commonly used clinically to improve kidney function and delay disease progression. However, these drugs have some limitations. They often require large doses, have no specific distribution in the kidneys, and bring many adverse reactions. For example, triptolide has a wide range of effects and high activity, making it a very promising anti-inflammatory and anti-fibrotic drug. However, it has poor water solubility, a narrow therapeutic window, no tissue selectivity in the body, and severe toxic side effects, which greatly limit its clinical use.

[0004] Constructing a kidney-targeted delivery system to selectively deliver drugs to the disease site and reduce their distribution in other tissues and organs is of great significance for enhancing therapeutic effects and reducing toxic side effects. Renal tubular epithelial cells are a 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 kidney 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 existence 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) or T cell immunoglobulin mucin domain, is a type 1 transmembrane protein induced by ischemia and toxic injury. KIM-1 is a functional phospho-serine receptor that binds and mediates the uptake of apoptotic cell bodies and is significantly upregulated in injured renal proximal tubules. Therefore, KIM-1 plays a crucial role in renal tubular epithelial cell injury (PTC) and the progression of chronic kidney disease, serving as both a therapeutic target and a delivery vehicle.

[0006] Biomimetic high-density lipoprotein nanoparticles, primarily composed of phospholipids and apolipoproteins, mimic endogenous high-density lipoprotein and are ideal delivery vehicles, boasting advantages such as small particle size, good biocompatibility, high safety, and ease of preparation. Currently, they are commonly used for tumor targeting, lymph node targeting, and liver targeting due to their specific targeting of the scavenger receptor B-1 (SRB-1 receptor).

[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 present invention aims to provide a novel use of biomimetic high-density lipoprotein nanoparticles, specifically their use in the preparation of drugs targeting hepatitis A virus receptor-1. For example, using biomimetic high-density lipoprotein nanoparticles to co-deliver anti-inflammatory and anti-fibrotic drugs to damaged renal tubular epithelial cells with high KIM-1 expression can effectively alleviate kidney damage, reduce renal fibrosis, and slow the progression of chronic kidney disease.

[0009] To achieve the above-mentioned purpose, the present invention provides the following technical solutions:

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

[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, which is DWFKAFYDKVAEKFKEAF, and 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-type 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-type 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 biomimetic high-density lipoprotein nanoparticle, which is composed of phospholipids and apolipoprotein mimetic peptides. The apolipoprotein mimetic peptide is an ApoA-I mimetic 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 bionic high-density lipoprotein nanoparticles is 15 nm to 35 nm.

[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 increase its therapeutic window. As a carrier with high biocompatibility, biomimetic 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 peptides 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 vary 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, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0026] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within 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 the 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 the kidney tissues of various chronic kidney disease model mice and normal mice in the WB experiment.

[0029] Figure 3 This is a diagram of Havcr1 gene expression 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 Figure 3 shows 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 of the uptake of DiD-bHDL 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 damaged HK-2 cells.

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

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

[0037] Figure 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] Figure 12 This is a graph showing the kidney injury scores of UUO model mice treated with different drugs.

[0039] Figure 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 commercial products.

[0041] During preliminary experiments, the inventors screened the types and ratios of phospholipids and apolipoprotein-mimicking peptides and found that dimyristoylphosphatidylcholine (DMPC) performed best as the phospholipid. Furthermore, a 2:1 mass ratio of phospholipid to apolipoprotein-mimicking peptide (a peptide with the sequence DWFKAFYDKVAEKFKEAF (SEQ ID NO. 1), hereinafter referred to as the "4F peptide") yielded nanoparticles with the optimal particle size. The following experiments used nanoparticles with this optimal type and ratio as examples.

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

[0043] 10 mg of DMPC was dissolved in chloroform and the organic solvent was removed by rotary evaporation at 37°C to form a film. PBS was then added to hydrate the film. Then, an aqueous solution containing 5 mg of 4F peptide was added and ultrasonically mixed to obtain the biomimetic HDL nanoparticles. TEM observations showed that the resulting biomimetic HDL nanoparticles had a particle size of 15 to 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 Nintedanib-loaded biomimetic high-density lipoprotein nanoparticles (BIBF-bHDL)

[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 product.

[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 ultrasonically treated to obtain the liposome (cholesterol only plays the role of stabilizing liposomes).

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

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

[0054] Healthy male Balb / C mice were used to establish a ureteral ligation (UUO) model, a folic acid-induced nephropathy (Folic acid) model, and an adenine-induced nephropathy (ADE) model (all established according to conventional experimental methods performed by those skilled in the art). Kidneys from each renal model mouse, as well as those from healthy controls (Normal group, also known as the Control group), were immunofluorescently labeled for KIM-1 protein expression. Western blotting (WB) and RT-qPCR were used to examine KIM-1 protein and gene expression in 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 KIM-1 expression in the kidneys of various model mice 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 showed that KIM-1 was 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 models (UUO models) were constructed using healthy male Balb / C mice and used for distribution experiments. To label the in vivo distribution of biomimetic high-density lipoprotein nanoparticles, nanoparticles loaded with the dye DiD (DiD-bHDL) of Example 1 were prepared, and liposome nanoparticles loaded with the dye DiD (DiD-liposome) of Comparative Example 1 and free DiD were used as controls. Two hours after tail vein injection, various tissues and organs were dissected and placed on a living body imaging device to observe the fluorescence distribution and perform semi-quantitative analysis. The results are shown in Figure 2. Figure 4 As shown in the figure, compared with free DiD and DiD-liposome, the distribution of DiD-bHDL in the kidney is significantly higher than that in other organs.

[0061] Furthermore, the kidneys were frozen and immunofluorescently stained to investigate the distribution of nanoparticles inside the kidneys. The experimental results are as follows: Figure 5 As shown, DiD-bHDL is more distributed in renal 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 Figure 2, cisplatin-induced HK-2 cells (CDDP-induced HK-2Cell) significantly increased the uptake of DiD-bHDL; 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, a competitive inhibition experiment was conducted 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. Figure 9As shown in Figure 3, after KIM-1 antibody pretreatment (KIM-1antibody-pretreated) cells, the relative fluorescence intensity in the cells was significantly reduced compared to the untreated cell control group (Control), indicating that the ability of cells to take up DiD-bHDL was significantly reduced. Figure 10 As shown, after overexpressing KIM-1 in HK-2 cells, the fluorescence intensity in the overexpression group (OE-KIM-1HK2) significantly increased, indicating a significant increase in the cells' ability to uptake DiD-bHDL. These results indicate that higher KIM-1 expression in HK-2 cells leads to greater uptake of biomimetic HDL nanoparticles, while lower uptake suggests that the biomimetic HDL nanoparticles of the present invention target KIM-1 for their effects.

[0066] Using the liposome nanoparticles of comparative example 1 loaded with dye DiD (DiD-liposome) 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 using the Pearson coefficient. Figure 11 As shown in the graph, 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 biomimetic 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 model was constructed to investigate the therapeutic effect of the biomimetic high-density lipoprotein nanoparticles of the present invention as a drug carrier 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 (n=5): sham-operated mice were injected with PBS solution via 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 every two days for 14 consecutive days;

[0072] (3) Free TP solution group (n = 5): UUO model mice were injected with TP solution (dose calculated as TP, 0.2 mg / kg) through the 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 calculated as BIBF, 2 mg / kg) via the 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 calculated as 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 pathological conditions and fibrosis conditions.

[0079] In order to evaluate the degree of kidney damage, this study used a pathological scoring method to quantitatively analyze kidney lesions. Renal tissue sections were observed under an optical microscope, and the kidney damage index was comprehensively assessed based on pathological characteristics such as degeneration and necrosis of tubular epithelial cells, tubular dilatation, protein cast formation, fibrous tissue proliferation, and inflammatory cell infiltration. The scoring method uses a four-level grading method, where 0 points represent normal tissue structure with no obvious lesions; 1 point represents mild damage, 2 points represent mild damage, 3 points represent moderate damage, and 4 points represent severe damage. The experimental results showed that the degree of kidney damage 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 kidney damage in the mice in each treatment group was alleviated, and the scores were lower than those in the model group. Among them, the degree of damage in the TP / BIBF-bHDL treatment group was the lowest (such as Figure 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 / visual field area (pixel area). Figure 13 As shown in the data, 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 the targeted delivery of drugs to cells that highly express hepatitis A virus receptor-1 (including KIM-1, TIM-1, CD365 or HAVCR-1, etc.) using biomimetic high-density lipoprotein nanoparticles, and then treating the disease, in particular, the use of biomimetic 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 the lack of effective drugs for the treatment of chronic kidney disease, and also solves the problem of the difficulty in targeting renal tubular epithelial cells. The biomimetic 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 biomimetic 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 increase its therapeutic window. As a carrier with high biocompatibility, biomimetic 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. Use of biomimetic high-density lipoprotein nanoparticles in the preparation of a drug targeting damaged renal tubular epithelial cells that overexpress KIM-1; the biomimetic high-density lipoprotein nanoparticles are composed of phospholipids and an apolipoprotein-mimicking peptide; the apolipoprotein-mimicking peptide is an ApoA-I mimetic peptide, the sequence of which is shown in SEQ ID NO.

1.

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

3. The use according to claim 2, characterized in that The mass ratio of the apolipoprotein mimetic peptide to phospholipid is 1:

2.

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.

5. The use according to claim 4, characterized in that The phospholipid is dimyristoylphosphatidylcholine.

6. The use according to claim 1, characterized in that The drug targeting damaged renal tubular epithelial cells that highly express KIM-1 is a drug that uses biomimetic high-density lipoprotein nanoparticles as carriers to encapsulate active ingredients.

7. The use according to claim 6, characterized in that The active ingredients are anti-inflammatory, anti-fibrotic and / or gene-type 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-type active ingredients are antisense oligonucleotides or siRNA.

8. The use according to claim 7, characterized in that The active ingredients are triptolide and nintedanib.

9. The use according to claim 1, characterized in that The drug targeting damaged renal tubular epithelial cells that highly express KIM-1 is a drug for treating chronic kidney disease.

10. The use according to claim 9, characterized in that The drug for treating chronic kidney disease is a drug for delaying the progression of chronic kidney disease.

11. The use according to claim 10, characterized in that The drug for delaying the progression of chronic kidney disease is a drug for alleviating kidney damage and / or alleviating kidney fibrosis.

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