High-entropy alloy nanoparticle and application thereof

Abstract

The invention discloses a high-entropy alloy nanoparticle and application thereof. The nanoparticles are formed by specific noble metals, have multienzyme activity, and can effectively remove ROS (reactive oxygen species) at an inflammation part and remodel the free radical steady state of the inflammation part; the skin inflammation reaction can be inhibited by adjusting a JAK-STAT signal channel; skin inflammation caused by psoriasis can be relieved by down-regulating inflammatory factors IL-6, IL-17 and IL-23, and a new treatment scheme is provided for psoriasis treatment.

Description

Technical Field

[0001] The present invention relates to a high entropy alloy nanoparticle and application thereof, and in particular to a high entropy alloy nanoparticle with multiple types of enzyme activities and application thereof. Background Art

[0002] Psoriasis (commonly known as psoriasis) is a common chronic inflammatory skin disease that is prone to recurrence. It is a chronic immune-mediated disease that is affected by genetics and various environmental factors. Typical skin symptoms are red plaques with clear borders, accompanied by silvery-white raised scales, and sometimes pustules. Common affected areas include the scalp, extensor muscles of the limbs, lower back, and genitals. Severe skin lesions can also spread throughout the body and cause systemic complications such as rheumatism and cardiovascular disease. The incidence of psoriasis is still rising. Although the mortality rate of psoriasis is very low, there are still a large number of patients who are deeply troubled by psoriasis.

[0003] The pathogenesis of psoriasis involves excessive feedback activation of the acquired immune system. Inducing factors in the environment cause innate immune cells to release cytokines and activate myeloid dendritic cells (DCs). Activated myeloid DCs present antigens to T cells and release cytokines to promote the differentiation of helper T cells 17 (Th17) and Th1. Subsequently, cytokines are secreted to further activate keratinocytes, ultimately forming a feedback loop to amplify the inflammatory response, leading to the formation of plaque psoriasis lesions. One of the core signaling pathways that drives the secretion of the above-mentioned inflammatory factors has been confirmed to be the JAK-STAT pathway, and inhibitors targeting JAK family members (such as the JAK1 inhibitor upadacitinib, the TYK inhibitor deuterocelexinib, etc.) have also been widely used in the treatment of psoriasis. Although the above-mentioned inhibitors have achieved certain therapeutic effects, factors such as high prices, nonspecific delivery, poor epidermal retention, and poor safety have limited their application in related treatment options.

[0004] On the other hand, oxidative stress is increasingly believed to be related to the development of psoriasis. The imbalance of reactive oxygen species (ROS) not only directly damages skin cells and organelles, but also induces the expression of inflammatory cytokines, further enhancing skin inflammatory infiltration and leading to inflammatory epithelial system microenvironment disorders. In recent years, with the rapid development of nanomedicine, nanomedicines for the treatment of psoriasis have been studied more and more widely. The work of Academician Shi Jianlin's research group published in Nature Communications (Volume 14, 2023, page 6767) systematically demonstrated that iron single-atom nanozymes with multi-enzyme activities of catalase (CAT), superoxide dismutase (SOD) and ascorbate peroxidase (APX) can achieve long-term intervention in psoriasis by continuously removing overexpressed reactive oxygen species (ROS) and reshaping the inflammatory microenvironment. Although there have been many reports on the enzyme-like catalytic activity of multi-metal nanocrystals, common problems include: the correlation between the composition of metal nanozymes and the catalytic activity of enzymes is unclear, and the scavenging of different subtypes of free radicals by nanozymes in the pathological environment is random. These limitations result in nanozymes designed based on previous research strategies, while exhibiting the necessary ability to scavenge target free radicals (i.e., "good" enzyme activity), may induce side effects due to the existence of unnecessary enzyme catalytic ability, making it difficult to achieve the optimal therapeutic effect under multi-metal synergistic enzyme catalysis. Summary of the invention

[0005] Purpose of the invention: The first purpose of the present invention is to provide a high entropy alloy nanoparticle having multiple types of enzyme activities, and the second purpose is to provide a pharmaceutical application of the high entropy alloy nanoparticle.

[0006] Technical solution: The high entropy alloy nanoparticles described in the present invention are prepared by the following method:

[0007] (1) reacting a metal acetylacetonate with a reducing agent and a structure directing agent to prepare initial high entropy alloy nanoparticles;

[0008] (2) modifying the initial high entropy alloy nanoparticles prepared in step (1) with thiol-modified polyethylene glycol to obtain the high entropy alloy nanoparticles;

[0009] The metal acetylacetonate comprises at least two of the acetylacetonates of platinum, palladium, copper and iron, and the mass proportion of each metal element in the high entropy alloy nanoparticles is 0% to 100%.

[0010] High entropy alloy nanomaterials (HEANPs) have unique high entropy properties, and the various metal elements that constitute high entropy alloy nanomaterials are adjustable, so that they have enzyme-like catalytic activity, and also have the characteristics of accurately constructing enzyme-like activity by regulating their elemental composition. Based on this, the present invention designs HEANPs with at least four enzyme-like activities of glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and glucose oxidase (GOD). The tissue compatibility of multi-enzyme active high entropy alloys is improved by surface modification of PEG molecules. The designed material has a regulatory effect on different free radical subgroups, can reshape free radical homeostasis by clearing inflammatory ROS, and activate the negative regulatory activity of the JAK-STAT pathway, thereby exerting an anti-inflammatory effect and achieving the purpose of accurately intervening in the psoriasis microenvironment.

[0011] Preferably, the particle size of the high entropy alloy nanoparticles is below 50 nm.

[0012] More preferably, the particle size of the high entropy alloy nanoparticles is 5 to 25 nm.

[0013] Further preferably, the particle size of the high entropy alloy nanoparticles is selected from 5 nm, 6 nm, 8 nm, 10 nm, 12 nm, 15 nm, 18 nm, 20 nm or 25 nm.

[0014] Preferably, the metal acetylacetonate used in step (1) of the method for preparing high entropy alloy nanoparticles comprises acetylacetonate of platinum, palladium, copper and iron, and the mass ratio of platinum, palladium, copper and iron elements in the high entropy alloy nanoparticles is (11-64):(5-50):(3-49):(1-44).

[0015] Further preferably, the mass ratio of platinum, palladium, copper and iron elements in the high entropy alloy nanoparticles is (11-64):(5-50):(3-49):(3-44).

[0016] More preferably, the mass ratio of platinum, palladium, copper and iron elements in the high entropy alloy nanoparticles is (29-34):(42-50):(16-21):(3-7).

[0017] Still more preferably, the mass ratio of platinum, palladium, copper and iron elements in the high entropy alloy nanoparticles is (30-34):(42-47):(16-21):(3-7).

[0018] Further preferably, the mass ratio of platinum, palladium, copper and iron elements in the high entropy alloy nanoparticles is 30:47:16:7, 29:50:20:1, 34:42:21:3, 11:31:14:44, 24:5:49:22 or 64:22:3:11.

[0019] Preferably, the thiolated polyethylene glycol (PEG-SH) used in step (2) of the method for preparing high entropy alloy nanoparticles is selected from thiolated polyethylene glycol with an amino tail end (NH2-PEG-SH), thiolated polyethylene glycol with a methoxy tail end (mPEG-SH) or thiolated polyethylene glycol with a carboxyl tail end (COOH-PEG-SH).

[0020]

[0021] More preferably, the molecular weight of the thiolated polyethylene glycol is 2 to 10 kDa.

[0022] More preferably, the molecular weight of the thiolated polyethylene glycol is 2, 5 or 10 kDa.

[0023] Still more preferably, the thiolated polyethylene glycol is selected from 5kDa or 10kDa mPEG-SH, 5kDa or 10kDa NH2-PEG-SH, and 2kDa COOH-PEG-SH.

[0024] Preferably, the reducing agent used in step (1) of the method for preparing high entropy alloy nanoparticles is glucose and tungsten hexacarbonyl (W(CO)6) in a mass ratio of (0.5-5.2):1, the structure directing agent is hexadecyltrimethylammonium chloride (CTAC), and the mass ratio of hexadecyltrimethylammonium chloride to tungsten hexacarbonyl is (0.5-2.1):1.

[0025] More preferably, the mass ratio of glucose to tungsten hexacarbonyl is 0.5:1, 1:1, 1.4:1, 1.5:1 or 5.2:1.

[0026] More preferably, the mass ratio of hexadecyltrimethylammonium chloride to tungsten hexacarbonyl is 0.5:1, 0.9:1, 1:1, 2:1 or 2.1:1.

[0027] Specifically, the preparation process of the high entropy alloy nanoparticles of the present invention is as follows:

[0028] The metal acetylacetonate is dissolved in oleic acid, and mixed with glucose, hexacarbonyl tungsten and a structure directing agent by ultrasound, and then heated and stirred for a period of time to obtain a preliminary high entropy alloy nanomaterial, and then the surface of the initial product is functionalized by polyethylene glycol thiol molecules with different tail modifications to obtain the final high entropy alloy nanomaterial. The solution is heated to 180-300°C after ultrasonic mixing, including but not limited to 200°C, 220°C, 240°C, 260°C, 280°C or 300°C; and then reacted for 45-120min, including but not limited to 45min, 60min, 75min, 90min or 105min.

[0029] The high entropy alloy nanoparticles of the present invention are used in preparing medicines for treating psoriasis.

[0030] Preferably, the drug is a drug for treating any of the following symptoms:

[0031] (1) Psoriatic skin inflammation;

[0032] (2) Skin damage;

[0033] (3) Skin erythema, scaling, and infiltration.

[0034] Preferably, the drug is a drug having at least four enzyme activities of glutathione S-transferase, superoxide dismutase, catalase, peroxidase, and glucose oxidase.

[0035] Preferably, the drug is a drug that removes inflammatory ROS and inhibits the JAK-STAT signaling pathway.

[0036] Preferably, the drug is a drug having any of the following functions:

[0037] (1) Inhibit excessive proliferation of epidermal keratinocytes;

[0038] (2) Improve the erythema area, skin thickness, and scar area of ​​psoriasis-like skin;

[0039] (3) Inhibits the thickening of the epidermis and shortening of spinous processes in psoriatic skin;

[0040] (4) Downregulate the expression level of inflammatory factors in psoriatic skin.

[0041] More preferably, the inflammatory factors include IL-6, IL-17 or IL-23.

[0042] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0043] The present invention uses specific precious metals to form a high-entropy alloy nanomaterial with uniform morphology and biocompatibility. The high-entropy alloy nanomaterial has multi-enzyme activity, can effectively remove ROS at the inflammatory site, reshape the free radical homeostasis at the inflammatory site, and effectively alleviate psoriasis symptoms; it can also inhibit skin inflammatory response by regulating the JAK-STAT signaling pathway; it can also alleviate psoriasis skin inflammation by downregulating IL-6, IL-17 and IL-23 inflammatory factors, providing a new treatment option for psoriasis. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 This is an X-ray photoelectron spectroscopy (XPS) diagram of the high entropy alloy nanomaterial prepared in Example 1;

[0045] Figure 2 This is a transmission electron microscopy (TEM) image of HEANPs-1 prepared in Example 1;

[0046] Figure 3 This is a transmission electron microscopy (TEM) image of HEANPs-6 prepared in Example 6;

[0047] Figure 4 The enzyme activity results of the high entropy alloy nanomaterials prepared in Examples 1 to 3;

[0048] Figure 5 The photos of the back skin of mice in the modeling group, control group and nanomaterial treatment group in Example 8;

[0049] Figure 6 The PASI total score and the erythema, thickness and scaling scores of the back skin lesions of mice in Example 8 over time are shown;

[0050] Figure 7 The results of the mRNA expression levels of IL-6, IL-17 and IL-23 in mouse skin in Example 8;

[0051] Figure 8 The transcriptome analysis results of the hyperkeratosis stimulated group (IL-6), the IL-6 stimulation combined with nanomedicine treatment group (IL-6+NPs), and the normal cell nanomedicine treatment group (Control) in Example 9. DETAILED DESCRIPTION

[0052] The technical solution of the present invention is further described below in conjunction with embodiments.

[0053] Example 1

[0054] (1) Synthesis of high entropy alloy nanoparticles

[0055] CTAC (8.8 mg) was added as a structure directing agent to an oleylamine (5 mL) solution containing Pt(acac)2 (2.2 mg), Pd(acac)2 (1.7 mg), Cu(acac)2 (1.5 mg), Fe(acac)3 (2.0 mg), glucose (12 mg) and W(CO)6 (8.8 mg), and ultrasound was performed to promote its dispersion and dissolution. The mixture was heated to 200 ° C in a sand bath (DLAB, China) and reacted for 1 h under magnetic stirring at 400 rpm. The resulting black product was collected by centrifugation, washed several times with an acetone / cyclohexane mixture (1:3, vol / vol) and stored in cyclohexane for further use.

[0056] (2) Surface modification of high entropy alloy nanoparticles

[0057] Take 1 mL of 10 mg / mL mPEG-SH (5 kDa, Jiankai Technology) polymer solution and add 1 mL of nanoparticle suspension (10 16 / mL), and shake at room temperature for 6 hours. Centrifuge at 17000 rpm for 30 minutes and collect the precipitate, wash it three times with ultrapure water, and then store the ligand-modified high entropy alloy material (named HEANPs-1) at 4°C in the dark for later use.

[0058] Figure 1 This is an X-ray photoelectron spectroscopy (XPS) diagram of the high entropy alloy nanomaterial prepared in Example 1. Figure 1 It can be seen that high entropy alloy nanomaterials are composed of four elements: Pt, Pd, Cu, and Fe.

[0059] Figure 2 This is a transmission electron microscope (TEM) image of HEANPs-1 prepared in Example 1. Figure 2 It can be seen that the high entropy alloy nanomaterial is a monodisperse nanosphere of uniform size with a diameter of about 6nm.

[0060] Example 2

[0061] (1) Synthesis of high entropy alloy nanoparticles

[0062] CTAC (8.8 mg) was added as a structure directing agent to an oleylamine (5 mL) solution containing Pt(acac)2 (2.0 mg), Pd(acac)2 (2.0 mg), Cu(acac)2 (1.5 mg), Fe(acac)3 (1.2 mg), glucose (12 mg) and W(CO)6 (8.8 mg), and ultrasound was performed to promote its dispersion and dissolution. The mixture was heated to 200 ° C in a sand bath (DLAB, China) and reacted for 1 h under magnetic stirring at 400 rpm. The resulting black product was collected by centrifugation, washed several times with an acetone / cyclohexane mixture (1:3, vol / vol) and stored in cyclohexane for further use.

[0063] (2) Surface modification of high entropy alloy nanoparticles

[0064] Take 1 mL of 10 mg / mL mPEG-SH (5 kDa, Jiankai Technology) polymer solution and add 1 mL of nanoparticle suspension (10 16 / mL), and reacted at room temperature for 6 hours. Centrifuged at 17000 rpm for 30 minutes and collected the precipitate, which was washed three times with ultrapure water, and then the ligand-modified high entropy alloy material (named HEANPs-2) was stored at 4°C in the dark for later use.

[0065] Example 3

[0066] (1) Synthesis of high entropy alloy nanoparticles

[0067] CTAC (8.3 mg) was added as a structure directing agent to an OAM (5 mL) solution containing Pt(acac)2 (2.0 mg), Pd(acac)2 (1.5 mg), Cu(acac)2 (1.3 mg), Fe(acac)3 (1.8 mg), glucose (12 mg) and W(CO)6 (8.8 mg), and ultrasound was performed to promote its dispersion and dissolution. The mixture was heated to 200 °C in a sand bath (DLAB, China) and reacted for 1 h under magnetic stirring at 400 rpm. The resulting black product was collected by centrifugation, washed several times with an acetone / cyclohexane mixture (1:3, vol / vol) and stored in cyclohexane for further use.

[0068] (2) Surface modification of high entropy alloy nanoparticles

[0069] Take 1 mL of 10 mg / mL NH2-PEG-SH (5 kDa, Jiankai Technology) polymer solution and add 1 mL of nanoparticle suspension (10 16 / mL), and reacted at room temperature for 6 hours. Centrifuged at 17000 rpm for 30 minutes and collected the precipitate, which was washed three times with ultrapure water, and then the ligand-modified high entropy alloy material (named HEANPs-3) was stored at 4°C in the dark for later use.

[0070] Example 4

[0071] (1) Synthesis of high entropy alloy nanoparticles

[0072] CTAC (7.0 mg) was added as a structure directing agent to an OAM (5 mL) solution containing Pt(acac)2 (0.8 mg), Pd(acac)2 (1.5 mg), Cu(acac)2 (1.8 mg), Fe(acac)3 (3.5 mg), glucose (7.2 mg) and W(CO)6 (14.0 mg), and ultrasound was performed to promote its dispersion and dissolution. The above mixture was heated to 240 °C in a sand bath (DLAB, China) and reacted for 2 h under magnetic stirring at 400 rpm. The resulting black product was collected by centrifugation, washed several times with an acetone / cyclohexane mixture (1:3, vol / vol) and stored in cyclohexane for further use.

[0073] (2) Surface modification of high entropy alloy nanoparticles

[0074] Take 1 mL of 10 mg / mL mPEG-SH (10 kDa, Jiankai Technology) polymer solution and add 1 mL of nanoparticle suspension (10 16 / mL), and reacted at room temperature for 6 hours. Centrifuged at 17000 rpm for 30 minutes and collected the precipitate, which was washed three times with ultrapure water, and then the ligand-modified high entropy alloy material (named HEANPs-4) was stored at 4°C in the dark for later use.

[0075] Example 5

[0076] (1) Synthesis of high entropy alloy nanoparticles

[0077] CTAC (14.0 mg) was added as a structure directing agent to an OAM (5 mL) solution containing Pt(acac)2 (1.2 mg), Pd(acac)2 (0.8 mg), Cu(acac)2 (3.2 mg), Fe(acac)3 (2.4 mg), glucose (7.2 mg) and W(CO)6 (7.0 mg), and ultrasound was performed to promote its dispersion and dissolution. The above mixture was heated to 160 ° C in a sand bath (DLAB, China) and reacted for 1.5 h under magnetic stirring at 400 rpm. The resulting black product was collected by centrifugation, washed several times with an acetone / cyclohexane mixture (1:3, vol / vol) and stored in cyclohexane for further use.

[0078] (2) Surface modification of high entropy alloy nanoparticles

[0079] Take 1 mL of 10 mg / mL COOH-PEG-SH (2 kDa, Aladdin) polymer solution and add 1 mL of nanoparticle suspension (10 16 / mL), and shake at room temperature for 6 hours. Centrifuge at 17000 rpm for 30 minutes and collect the precipitate, wash it three times with ultrapure water, and then store the ligand-modified high entropy alloy material (named HEANPs-5) at 4°C in the dark for later use.

[0080] Example 6

[0081] (1) Synthesis of high entropy alloy nanoparticles

[0082] CTAC (17.0 mg) was added as a structure directing agent to an OAM (5 mL) solution containing Pt(acac)2 (7.5 mg), Pd(acac)2 (3.5 mg), Cu(acac)2 (1.8 mg), Fe(acac)3 (3.5 mg), glucose (42.5 mg) and W(CO)6 (8.2 mg), and ultrasound was performed to promote its dispersion and dissolution. The mixture was heated to 260 °C in a sand bath (DLAB, China) and reacted for 2 h under magnetic stirring at 400 rpm. The resulting black product was collected by centrifugation, washed several times with an acetone / cyclohexane mixture (1:3, vol / vol) and stored in cyclohexane for further use.

[0083] (2) Surface modification of high entropy alloy nanoparticles

[0084] Take 1 mL of 10 mg / mL NH2-PEG-SH (10 kDa, Jiankai Technology) polymer solution and add 1 mL of nanoparticle suspension (10 16 / mL), and shake at room temperature for 6 hours. Centrifuge at 17000 rpm for 30 minutes and collect the precipitate, wash it three times with ultrapure water, and then store the ligand-modified high entropy alloy material (named HEANPs-6) at 4°C in the dark for later use.

[0085] Figure 3 This is a transmission electron microscope (TEM) image of HEANPs-6 prepared in Example 6. Figure 3 It can be seen that the high entropy alloy nanomaterial is a monodisperse nanosphere of uniform size with a diameter of about 25nm.

[0086] Table 1 Elemental composition of high entropy alloy nanoparticles

[0087] sample Pt Pd Cu Fe HEANPs-1 30 47 16 7 HEANPs-2 29 50 20 1 HEANPs-3 34 42 21 3 HEANPs-4 11 31 14 44 HEANPs-5 24 5 49 22 HEANPs-6 64 22 3 11

[0088] Table 1 shows the mass ratios of various elements of the high entropy alloy nanomaterials prepared in Examples 1 to 6 obtained by inductively coupled plasma mass spectrometry (ICP-MS) analysis.

[0089] Example 7: Evaluation of enzyme-like activity of high entropy alloy nanomaterials

[0090] For the POD enzyme activity assay, 10.97 mg of 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) powder was first weighed and dissolved in 20 mL of deionized water to prepare 1 mM ABTS solution for further use. Then, the obtained ABTS solution (50 μL, 1 mM), potassium dihydrogen phosphate buffer (410 μL, pH 6.0), hydrogen peroxide H2O2 solution (50 μL, 0.4 mM) and nanomaterial sample (40 μL, 200 μg / mL) were mixed evenly. After a period of time, the reaction solution was immediately transferred and the absorbance was measured at 415 nm. GOD, SOD, CAT and GST enzyme activities were detected using detection kits purchased from Abbkine Technology Co., Ltd., and the corresponding experimental procedures were carried out according to the instructions given by the company. GST can promote the combination of glutathione (GSH) and 1-chloro-2,4-dinitrobenzene (CDNB), and the light absorption peak wavelength of the combined product is 340nm; by measuring the rate of increase of absorbance at a wavelength of 340nm, the activity can be calculated. The substrate of the SOD activity test kit is the superoxide anion free radical O2 ·-, SOD activity is measured by recording the colorimetric change at OD = 450nm. The CAT kit measures the activity of the nanozyme based on its reaction with methanol in the presence of H2O2. In this process, formaldehyde appears as an intermediate, and its concentration can be measured at OD = 540nm. The principle of GOD activity detection is that the oxidation of D-glucose produces hydrogen peroxide, which reacts with the chromophore in an acidic solution, and the concentration of the colored product can be measured at OD = 580nm.

[0091] Figure 4 The enzyme activity of the high entropy alloy nanomaterials prepared in Examples 1 to 3. Figure 4 It can be seen that high entropy alloy nanomaterials all have at least four enzyme activities among GST, SOD, CAT, POD, and GOD.

[0092] Example 8: Evaluation of the therapeutic effect of high entropy alloy nanoparticles on psoriasis

[0093] Six-week-old BALB / c mice were randomly divided into groups and maintained in an SPF environment with a 12-h light / dark cycle and provided with unlimited food and water. The imiquimod-induced psoriasis mouse model was established according to the classical method. In brief, mice in the modeling group (IMQ group) were topically applied with 62.5 mg of 5% imiquimod cream daily for 7 consecutive days. The control group mice used the same dose of vaseline cream. HEANPs-1 prepared in Example 1 or HEA NPs-2 prepared in Example 2 were subcutaneously injected on days 2 and 5 (10 points at the modeling site, 10 μL injection at a single point, concentration 200 μg / mL). The same dose of normal saline was used for the control group and imiquimod-induced psoriasis mice. Drawing on the clinical PASI score, the severity of psoriasis skin in each group of mice was quantified in a blinded manner 24 h after the last administration. The scoring criteria are as follows: 0: none; 1: mild; 2: moderate; 3: severe; 4: very severe. Mice were euthanized by cervical dislocation, and RNA from the psoriasis skin tissue on the back of mice was isolated and purified using Trizol reagent according to the manufacturer's instructions. The mRNA levels of inflammatory factors IL-6, IL-17, and IL-23 in the above tissue fluid were quantitatively detected by q-PCR.

[0094] Figure 5 The back skin conditions of mice in the modeling group, control group, and nanomaterial treatment group. Figure 5 It can be seen that the formation of scaly lesions on the back skin of mice treated with HEANPs-1 or HEANPs-2 was significantly alleviated, with only a small amount of skin lesions formed.

[0095] Further, Figure 6The skin lesions and inflammation during the treatment were evaluated based on quantitative indicators. The core indicators included erythema, skin thickness, scarring, and the comprehensive severity index (PASI) which is widely used as the gold standard. For the IMQ modeling group, the results showed that the degree of skin lesions in the treated mice continued to increase with the extension of modeling time, while the mice treated with high-entropy alloy nanomaterials showed a slow progression trend in multiple dimensions such as skin lesions and scabs. In addition, Figure 7 After being treated with high-entropy alloy nanoparticles, the levels of IL-6, IL-17 and IL-23 in the mouse skin tissue dropped to levels similar to those of healthy mice, indicating that the high-entropy alloy nanomaterials prepared by this method have a significant therapeutic effect on psoriasis.

[0096] Example 9: Transcriptomics analysis of the mechanism of high entropy alloy nanoparticles in treating psoriasis

[0097] HaCaT cells were seeded in a culture dish and incubated for 24 h, and then induced with IL-6 (10 ng / mL) to establish a psoriasis-like keratinocyte model (IL-6 group). The abnormally proliferated HaCat cells induced by IL-6 were washed with fresh cell culture medium and exposed to high entropy alloy nanoparticles HEANPs-2 (10 μg / mL) as a nanomedicine treatment group (IL-6+NPs). The cells were collected and the total RNA of the three groups of cells was isolated and purified using TRIzol according to the operating protocol provided by the manufacturer, and then transcriptomic analysis was performed by Lianchuan Biotechnology Co., Ltd. (China), and the obtained differential gene data were compared with the gene set (psoriasis) closely related to the onset and progression of psoriasis in the GeneCards public database (www.genecards.org). Figure 8 The Venn diagram and volcano diagram in the figure intuitively show that the changes in SOCS1 mRNA treated with high entropy alloy nanomaterials are significant, and are at the forefront of the gene set stimulated by high entropy alloy nanomaterials to up-regulate expression. In contrast, the transcription level of SOCS1 caused by IL-6 stimulation is reduced. SOCS1 is one of the three types of negative regulators of the JAK-STAT signaling pathway, a key signal axis of psoriasis. Therefore, high entropy alloys with four enzyme activities can achieve effective treatment of psoriasis by significantly activating the activity of the JAK-STAT negative regulatory signal axis.

Claims

1. A high entropy alloy nanoparticle, characterized in that: Prepared by the following method: (1) reacting a metal acetylacetonate with a reducing agent and a structure directing agent to prepare initial high entropy alloy nanoparticles; (2) modifying the initial high entropy alloy nanoparticles prepared in step (1) with thiol-modified polyethylene glycol to obtain the high entropy alloy nanoparticles; The metal acetylacetonate comprises at least two of the acetylacetonates of platinum, palladium, copper and iron, and the mass proportion of each metal element in the high entropy alloy nanoparticles is 0% to 100%.

2. The high entropy alloy nanoparticles according to claim 1, characterized in that: Its particle size is below 50nm.

3. The high entropy alloy nanoparticles according to claim 2, characterized in that: The particle size is selected from 5 to 25 nm.

4. The high entropy alloy nanoparticles according to claim 1, characterized in that: The metal acetylacetonate used in step (1) of the preparation method comprises acetylacetonate of platinum, palladium, copper and iron, and the mass ratio of platinum, palladium, copper and iron elements in the high entropy alloy nanoparticles is (11-64):(5-50):(3-49):(1-44).

5. The high entropy alloy nanoparticles according to claim 4, characterized in that: The mass ratio of platinum, palladium, copper and iron elements in the high entropy alloy nanoparticles is 30:47:16:7, 29:50:20:1, 34:42:21:3, 11:31:14:44, 24:5:49:22 or 64:22:3:

11.

6. The high entropy alloy nanoparticles according to claim 1, characterized in that: The thiolated polyethylene glycol used in step (2) of the preparation method is selected from thiolated polyethylene glycol having an amino tail end, a methoxy tail end or a carboxyl tail end.

7. The high entropy alloy nanoparticles according to claim 6, characterized in that: The molecular weight of the thiolated polyethylene glycol is 2-10 kDa.

8. The high entropy alloy nanoparticles according to claim 1, characterized in that: The reducing agent used in step (1) of the preparation method is glucose and tungsten hexacarbonyl in a mass ratio of (0.5-5.2):1, the structure directing agent is hexadecyltrimethylammonium chloride, and the mass ratio of hexadecyltrimethylammonium chloride to tungsten hexacarbonyl is (0.5-2.1):

1.

9. Use of the high entropy alloy nanoparticles according to claim 1 in preparing a drug for treating psoriasis.

10. The use according to claim 9, characterized in that: The medicine is a medicine for treating any of the following symptoms: (1) Psoriatic skin inflammation; (2) Skin damage; (3) Skin erythema, scaling, and infiltration.

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