Hollow iron-based nanozyme, drug delivery system, preparation method and application thereof

Abstract

The present invention relates to a hollow iron-based nanozyme, a drug delivery system, and its preparation method and application. The hollow iron-based nanozyme is prepared by stirring tetraethoxysilane, anhydrous ethanol, deionized water, and ammonia at room temperature to obtain nano-SiO2; the nano-SiO2 and a trivalent soluble iron salt are then dispersed in deionized water to obtain a mixed solution I, and then a NaBH4 aqueous solution is slowly added under stirring, and the final mixture is reacted at 70-90°C. The hollow iron-based nanozyme can better consume GSH and load drugs. Based on this, a drug delivery system is designed, which significantly enhances the anti-tumor immune response through the synergistic activation of ferroptosis and the cGAS-STING pathway.

Description

Technical Field

[0001] The present invention belongs to the field of medical materials, and specifically relates to a hollow iron-based nanozyme, a drug delivery system, and a preparation method and application thereof. Background Art

[0002] Lymphoma is one of the malignant tumors with the highest incidence worldwide. Although traditional chemotherapy and radiotherapy have achieved certain therapeutic effects, their efficacy is often limited in cases with advanced or extensive metastasis. This is mainly attributed to the immunosuppressive properties of the tumor microenvironment (TME), as well as the tolerance and escape mechanisms of tumor cells to treatment. This immunosuppressive TME is usually manifested by insufficient tumor-infiltrating lymphocytes (TILs), excessive accumulation of immunosuppressive cells (such as myeloid suppressor cells and regulatory T cells), and inefficient antigen presentation, which greatly weakens the anti-tumor immune response. In recent years, the development of new strategies that can effectively reshape the TME and stimulate lasting anti-tumor immune responses has become one of the important directions of tumor immunotherapy.

[0003] As an important pathway of innate immunity, the cyclic guanosine monophosphate-adenosine monophosphate synthase stimulator (cGAS-STING) signaling pathway activates adaptive immunity by recognizing double-stranded DNA (dsDNA) in the cytoplasm, inducing the production of type I interferon (IFN-I) and proinflammatory cytokines. This pathway can not only effectively activate dendritic cells (DCs), but also stimulate cytotoxic T lymphocytes (CTLs) to infiltrate tumor sites and enhance anti-tumor immunity. However, in tumor treatment, the activation of the cGAS-STING pathway still faces many challenges: first, the amount of dsDNA released in the cytoplasm is often insufficient, which cannot provide enough signaling molecules and makes it difficult to effectively activate cGAS; second, cGAS has a low sensitivity to dsDNA binding, resulting in low activation efficiency of the pathway. High concentrations of GSH and hypoxic environments also inhibit the immune activation process triggered by treatment.

[0004] In addition, tumor cells often suppress the continued activation of the pathway by increasing glutathione (GSH) levels or enhancing DNA repair capacity. These limitations suggest that it may be difficult to fully stimulate anti-tumor immune responses by activating the cGAS-STING pathway alone.

[0005] Ferroptosis is a non-apoptotic cell death mechanism driven by excessive accumulation of intracellular reactive oxygen species (ROS) and lipid peroxidation (LPO). Studies have shown that ferroptosis can release tumor-associated antigens and danger signaling molecules, thereby inducing immunogenic cell death (ICD) and stimulating a potent anti-tumor immune response. Furthermore, ferroptosis-induced mitochondrial damage can release mitochondrial DNA (mitoDNA), further promoting activation of the cGAS-STING pathway, forming a positive feedback loop for the immune response.

[0006] However, most of the existing nanozyme systems based on ferroptosis are solid structures with limited surface drug loading, and the release rate of iron ions is uncontrollable, which may lead to systemic toxicity. In addition, some materials have poor stability in the TME, making it difficult to achieve drug loading, controlled release, and ferroptosis induction at the same time. In summary, the induction efficiency of ferroptosis by existing materials is low, and they cannot fully trigger tumor immunogenic cell death (ICD), resulting in a weak adaptive immune response. High GSH levels in the TME will scavenge reactive oxygen species (ROS) produced by treatment and reduce the incidence of lipid peroxidation (LPO). The release efficiency of iron ions is unstable, making it difficult to continuously induce ferroptosis. GPX4 overexpression protects tumor cells from lipid peroxidation damage and inhibits the ferroptosis process.

[0007] Moreover, there is currently a lack of systematic solutions on how to effectively induce ferroptosis and synergistically combine it with cGAS-STING pathway activation to achieve precise immune regulation of tumors. Summary of the Invention

[0008] To overcome the above obstacles, this study synthesized an iron-based nanozyme and then proposed a new smart drug delivery system (DDS) based on this hollow iron-based nanozyme, which can effectively induce ferroptosis and activate the cGAS-STING pathway, thereby achieving precise immune regulation of tumors.

[0009] The specific technical solutions of the present invention are as follows:

[0010] In a first aspect of the present invention, a hollow iron-based nanozyme is provided, wherein the hollow iron-based nanozyme is prepared by the following method:

[0011] Tetraethoxysilane, anhydrous ethanol, deionized water and ammonia water were stirred and reacted at room temperature to obtain nano-SiO2;

[0012] The nano-SiO2 and trivalent soluble iron salt prepared above were dispersed in deionized water to obtain a mixed solution I. Subsequently, a NaBH4 aqueous solution was slowly added under stirring, and the final mixture was reacted at 70-90°C to obtain the hollow iron-based nanozyme HFeS.

[0013] The obtained hollow iron-based nanozyme HFeS has excellent peroxidase-like (POD) and Fenton catalytic activity. In TME, HFeS can consume GSH and generate a large amount of Fe2+ by reacting with high levels of GSH, thereby producing hydroxyl radicals (·OH) through the Fenton reaction, inducing ferroptosis. In addition, hydroxyl radicals and oxidative stress can trigger the release of mitochondrial DNA and damage nuclear DNA, thereby further activating the cGAS-STING pathway. It can consume GSH and alleviate the antioxidant and immunosuppressive properties of TME. It regulates redox homeostasis, reduces the immunosuppressive state of tumor tissue, promotes the infiltration and activation of immune cells, and improves the tumor microenvironment. Moreover, the hollow nanozyme is also conducive to drug loading.

[0014] In a preferred embodiment, the volume ratio of tetraethoxysilane: anhydrous ethanol: deionized water: ammonia water is 1.0-2.0: 20-30: 1.5-3: 0.3-0.6, the reaction time is 12-16 hours, and the ammonia water is 25-28%.

[0015] In a preferred embodiment, in the mixed solution I, the SiO2 content is 0.3-10 mg / mL, the Fe3+ content is 0.0015-0.0075 mmol; the concentration of the NaBH4 aqueous solution is 110-240 mg / mL; according to the volume ratio, the mixed solution I:NaBH4 aqueous solution = 20-30:2.5-3.5, and the reaction time is 6-10 h.

[0016] The second aspect of the present invention provides the use of the hollow iron-based nanozyme in the preparation of anti-tumor drugs.

[0017] The third aspect of the present invention provides a drug delivery system comprising the hollow iron-based nanozyme. The drug delivery system uses the above-mentioned hollow iron-based nanozyme as a core carrier, is loaded with a chemotherapy drug and a STING signaling pathway agonist, and is coated with a tumor cell membrane. The chemotherapy drug increases the level of cytoplasmic dsDNA by nuclear DNA damage, and the STING signaling pathway agonist enhances the immune response by directly activating the STING signal. It can synergistically raise the cytoplasmic dsDNA level and activate the STING signal together with the hollow iron-based nanozyme core carrier.

[0018] Tumor cell membrane coating technology can give nanocarriers a "camouflage" ability, leveraging homologous adhesion molecules on the membrane surface to achieve precise delivery to tumor tissue. Furthermore, the cell membrane can effectively evade recognition by the immune system, extending the nanocarrier's circulation time in the body and improving drug delivery efficiency.

[0019] The fourth aspect of the present invention provides the use of the drug delivery system in the preparation of anti-tumor drugs.

[0020] The fifth aspect of the present invention provides a lymphoma drug delivery system, which uses the hollow iron-based nanozyme as a core carrier, is loaded with the chemotherapy drug DOX and the STING signaling pathway agonist MSA-2, and is coated with a lymphoma cell membrane.

[0021] A sixth aspect of the present invention provides a method for preparing the lymphoma drug delivery system, comprising the steps of:

[0022] (1) Preparation of HFeS / DOX-loaded nanozymes:

[0023] The chemotherapy drug DOX dispersion was added dropwise to the HFeS dispersion and stirred at room temperature to obtain the drug-loaded nanozyme HFeS / DOX.

[0024] (2) Preparation of HFeS / DOX / MSA-2 drug-loaded nanozymes:

[0025] HFeS / DOX and MSA-2 were dispersed in acetone, and the mixture was stirred at room temperature until 2 / 3 of the solvent evaporated, and then washed with ultrapure water to obtain HFeS / DOX / MSA-2;

[0026] (3) Preparation of cell membrane-modified drug-loaded nanozyme CM@HFeS / DOX / MSA-2:

[0027] The cancer cell membrane fragments were mixed with the HFeS / DOX / MSA-2 drug-loaded nanozymes prepared above, and CM@HFeS / DOX / MSA-2 was prepared by co-extrusion.

[0028] Preferably, in step (1), the concentration of the DOX dispersion is 3-7.5 mg / mL, the concentration of the HFeS dispersion is 1.5-2.5 mg / mL, and V DOX分散液 :V HFeS分散液 =0.8-1.2:8-12, stirring reaction time is 12-24h.

[0029] Preferably, in step (2), the weight ratio is HFeS / DOX:MSA-2=8-12:4-6.

[0030] The beneficial effects of the present invention are:

[0031] Compared to existing technologies, this invention, based on the synthetic hollow iron-based nanozyme HFeS, has designed an intelligent drug delivery system centered on HFeS. This system significantly enhances anti-tumor immune responses through synergistic activation of ferroptosis and the cGAS-STING pathway. This system not only possesses unique advantages in improving the tumor microenvironment and promoting immune cell infiltration, but also, through its multifunctional synergy, provides a solution with potential clinical translational value for the precision treatment of systemic lymphoma. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 This is a transmission electron micrograph of CM@HFeS / DOX / MSA-2 synthesized in an embodiment of the present invention;

[0033] Figure 2 is the UV curve of GSH consumption at different concentrations of HFeS;

[0034] Figure 3 Flow cytometry histograms of HUVEC, L929, MB49, and A20 cells treated with CM@HFeS / DOX / MSA-2 (A); Fluorescence quantitative histograms in different cells (B);

[0035] Figure 4 The cytotoxicity of different concentrations of CM@HFeS on L929 (A); the cytotoxicity of CM@HFeS, CM@HFeS / DOX and CM@HFeS / DOX / MSA-2 on A20 (B). DETAILED DESCRIPTION

[0036] The present invention synthesizes a hollow iron-based nanozyme, and the preparation method is as follows:

[0037] Tetraethoxysilane, anhydrous ethanol, deionized water and ammonia water were stirred and reacted at room temperature to obtain spherical nano-SiO2;

[0038] The spherical nano-SiO2 and trivalent soluble iron salt prepared above were dispersed in deionized water to obtain a mixed solution I. Subsequently, a NaBH4 aqueous solution was slowly added under stirring, and the final mixture was reacted at 70-90°C to obtain the hollow iron-based nanozyme HFeS.

[0039] The present invention forms a hollow structure by etching spherical nano-SiO2 with trivalent iron, which provides a higher specific surface area and drug loading efficiency, significantly increasing the therapeutic dose. HFeS can be controlled to degrade in the acidic environment of TME, releasing Fe2 + Precisely inducing ferroptosis prevents excessive ROS production from causing normal tissue damage. Compared to traditional nanozymes, the HFeS of this invention combines efficient drug loading and TME responsiveness, forming the core of the subsequent design of multifunctional nanotherapy platforms.

[0040] At the same time, based on the hollow iron-based nanozyme, the present invention designed a drug delivery system. The hollow iron-based nanozyme is used as a core carrier, loaded with chemotherapy drugs and STING signaling pathway agonists, and coated with tumor cell membranes. The chemotherapy drugs increase the level of cytoplasmic dsDNA by damaging nuclear DNA, and the STING signaling pathway agonists enhance the immune response by directly activating the STING signal. Together with the hollow iron-based nanozyme core carrier, they can synergistically raise the level of cytoplasmic dsDNA and activate the STING signal.

[0041] This drug delivery system, through the co-existence of chemotherapy drugs and STING signaling pathway agonists, has the dual effects of chemotherapy and immunotherapy. The Fenton reaction of nanozymes generates ROS, which further enhances the ICD effect induced by DOX, providing a stronger initial stimulation signal for immunotherapy. The release of MSA-2 is precisely controlled by TME conditions, ensuring its immune activation effect at the tumor site rather than systemic distribution and side effects, thus overcoming the existing chemotherapy and immunotherapy combination strategies, in which drug carriers usually only deliver chemotherapy drugs or immune activators alone, lacking effective synergistic treatment design. The efficacy of some immune activators is limited by their delivery efficiency, making it difficult to produce efficient immune stimulation at the tumor site.

[0042] Furthermore, HFeS can precisely release drugs by responding to weak acidity and high GSH levels. The release rate of the loaded material is regulated according to the TME, ensuring effective drug concentration in the tumor area while minimizing damage to normal tissues.

[0043] At the same time, coating tumor cell membranes can leverage the specific targeting effects of membrane proteins to achieve precise tumor identification and drug delivery. Furthermore, cell membrane modification can effectively circumvent recognition by the host immune system, improving drug delivery efficiency. This overcomes the shortcomings of existing drug delivery systems, which generally rely on chemical modification or antibody coupling for targeting, which are susceptible to clearance by the host immune system and result in low targeting efficiency.

[0044] Furthermore, the tumor cell membrane coating of the present invention improves the drug delivery system's affinity for tumor tissue and enhances its ability to escape the immune system, significantly increasing the efficiency of drug accumulation at the tumor site. Compared with traditional chemical targeting strategies, the cell membrane modification technology of the present invention is more biocompatible and stable, reducing the toxicity caused by chemical modification.

[0045] Specifically, the present invention provides a lymphoma drug delivery system, which uses the hollow iron-based nanozyme as a core carrier, is loaded with the chemotherapy drug DOX and the STING signaling pathway agonist MSA-2, and is coated with a lymphoma cell membrane.

[0046] In summary, in order to overcome the shortcomings of existing technologies in drug delivery efficiency, immune activation, and targeting accuracy, the present invention, through the construction of multifunctional nanocarriers, combines the synergistic mechanism of chemotherapy, immunotherapy, and ferroptosis induction, adopts a comprehensive scheme of hollow structure design, combined drug loading, homologous targeted modification, and TME-responsive release, significantly improving the anti-tumor therapeutic effect and providing a new technical path for multimodal combined treatment of tumors.

[0047] The present invention is further described below with reference to specific examples, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art. Unless otherwise specified, the reagents and materials used in the following examples are commercially available. Example 1 Preparation of hollow iron-based nanozyme HFeS

[0048] (1) Preparation of SiO2

[0049] 1 mL of TEOS, 25 mL of anhydrous ethanol, 2 mL of deionized water, and 0.5 mL of 25-28% ammonia were stirred at room temperature for 14 h. The white precipitate was washed several times with anhydrous ethanol and deionized water, and then collected by centrifugation (8000 rpm, 10 min).

[0050] (2) Preparation of HFeS nanozymes

[0051] 150 mg of SiO2 and 0.10 mmol of FeCl3·6H2O were ultrasonically dissolved in 27 mL of deionized water. Subsequently, an aqueous solution of NaBH4 (500 mg in 3 mL of ice-cold deionized water) was slowly added to the mixture with stirring. The final mixture was reacted in a 20 mL reactor at 80°C for 8 h, and the product was then purified by three consecutive wash / centrifugation cycles (10,000 rpm) using anhydrous ethanol and deionized water.

[0052] Example 2 Preparation of CM@HFeS / DOX / MSA-2

[0053] (1) Preparation of HFeS / DOX-loaded nanozymes

[0054] 5 mg of DOX was weighed and dissolved in 1 mL of pure water, and then added dropwise to the above-mentioned 10 mL, 2 mg / mL HFeS nanozyme dispersion, stirred overnight at room temperature, centrifuged and washed with water several times to obtain the drug-loaded nanozyme HFeS / DOX.

[0055] (2) HFeS / DOX (10 mg) and MSA-2 (5 mg) were dispersed in acetone in an open flask, and the mixture was stirred at room temperature until 2 / 3 of the volume of the solvent evaporated, and then the product was washed three times with ultrapure water to obtain HFeS / DOX / MSA-2.

[0056] (3) Preparation of cell membrane-modified drug-loaded nanozymes (CM@HFeS / DOX / MSA-2)

[0057] The cell membrane is wrapped by extrusion.

[0058] First, the prepared cancer cell membrane fragments were evenly dispersed in deionized water. HFeS / DOX / MSA-2 was then added, and the mixture of cell membrane fragments and HFeS / DOX / MSA-2 was coextruded sequentially through polycarbonate filters with different pore sizes (1 μm, 0.8 μm, and 0.45 μm) using an Avanti liposome extruder. Finally, the extruded mixture was centrifuged at 8000 rpm for 10 minutes to collect CM@HFeS / DOX / MSA-2.

[0059] Comparative Example 1 Preparation of CM@HFeS

[0060] Referring to the method of Example 2, steps (1) and (2) were omitted, and HFeS was directly mixed with cell membrane fragments and CM@HFeS was prepared by extrusion.

[0061] Comparative Example 2 Preparation of CM@HFeS / DOX

[0062] Referring to the method of Example 2, step (2) was omitted and HFeS / DOX was directly mixed with cell membrane fragments to prepare CM@HFeS / DOX by extrusion.

[0063] Test Case

[0064] (1) TEM characterization

[0065] Figure 1 This is a transmission electron micrograph of the cell membrane-modified drug-loaded nanozyme CM@HFeS / DOX / MSA-2 obtained in Example 2. It can be seen that the nanozyme obtained after 8 hours of ferric chloride etching in Example 1 is a hollow iron-doped SiO2 sphere. The formation of the hollow structure after etching may be due to a dissolution-regrowth process.

[0066] (2) GSH consumption

[0067] DTNB was used to evaluate the GPx-like activity of the HFeS nanozyme obtained in Example 1.

[0068] Solutions of HFeS particles at different concentrations (0, 50, 75, 100, 125, 150, and 250 μg / mL) were dispersed in 10 mmol / L GSH buffer at pH 4.5. After 12 hours, the supernatant was removed and reacted with 1 mg / mL DTNB solution for 30 minutes. The absorbance of each group was immediately measured at 412 nm using a UV-visible spectrophotometer.

[0069] like Figure 2 As shown in Figure 3, the DTNB absorbance decreased significantly with the increase of nanozyme concentration, indicating that HFeS nanozyme effectively consumed GSH through GPx-like activity.

[0070] In summary, it can be seen that the iron-doped HFeS nanozyme synthesized in Example 1 has a hollow structure and can consume GSH.

[0071] (3) Homologous targeting

[0072] Flow cytometry was used to evaluate the cellular uptake of CM@HFeS / DOX obtained in Example 2 in four cell types: MB49, HUVEC, L929, and A20.

[0073] Specifically, 1×10 5 Cells were cultured overnight to allow for adhesion. CM@HFeS / DOX (0.5 mL, 50 μg / mL) was added to the cells and incubated for 4 h. The original culture medium was then aspirated and the cells were washed three times with PBS. Paraformaldehyde was added to fix the cells for 10 minutes and stained with DAPI for 15 minutes. After incubation, the cells were washed three times with PBS and analyzed by flow cytometry. Figure 3 As shown in A and B, the cancer cell membrane biomimetic camouflage strategy facilitates targeting, thereby promoting the active uptake of the biomimetic camouflaged nanodrug by homologous cancer cells. Flow cytometry was used to quantify the uptake of CM@HFeS / DOX in each cell line. The mean fluorescence intensity of homologous cells (A20) was approximately twice that of heterologous cells (e.g., MB49).

[0074] (2) Cytotoxicity

[0075] A. The cytotoxicity of CM@HFeS on L929 cells was evaluated by CCK-8 assay for cell viability.

[0076] The specific operation steps are as follows: First, L929 cells are seeded in a 96-well plate at a density of 5000 cells / well, and then placed in a carbon dioxide incubator to culture overnight. Subsequently, the original culture medium is aspirated and replaced with fresh complete culture medium containing different concentrations of CM@HFeS. The selected CM@HFeS concentration range is 0-200μg / mL, and each concentration has 3 parallels. Then culture in an incubator for 24h. After culture, the cells are washed once with PBS and 100μL of fresh culture medium (containing 10% CCK-8) is added to each well. Place in an incubator and incubate for a period of time. Finally, use a microplate reader to detect and record the absorbance at a wavelength of 450nm, and calculate the cell survival rate by the following formula:

[0077] Cell viability (%) = (absorbance of experimental group - absorbance of blank group) / (absorbance of negative control group - absorbance of blank group) × 100%.

[0078] The results are as follows Figure 4 As shown in Figure 5A, the viability of L929 cells remained above 80% after incubation with CM@HFeS for 24 h, which can be attributed to the satisfactory biocompatibility of CM@HFeS.

[0079] B. The CCK-8 method was used to detect cell activity to evaluate the cytotoxicity of CM@HFeS, CM@HFeS / DOX, and CM@HFeS / DOX / MSA-2 on A20 cells.

[0080] The specific operation steps are as follows: First, A20 is seeded in a 96-well plate at a density of 5000 cells / well, and then placed in a carbon dioxide incubator to culture overnight. Subsequently, the original culture medium is aspirated and replaced with fresh complete culture medium containing the sample. Then culture in the incubator for 24 hours. After culture, the cells are washed once with PBS and 100 μL of fresh culture medium (containing 10% CCK-8) is added to each well. Place in the incubator and incubate for a period of time. Finally, use a microplate reader to detect and record the absorbance at a wavelength of 450 nm. The cell viability is calculated by the following formula:

[0081] Cell viability (%) = (absorbance of experimental group - absorbance of blank group) / (absorbance of negative control group - absorbance of blank group) × 100%.

[0082] The results are as follows Figure 4 As shown in Figure B, compared with the control group, the CM@HFeS group showed an inhibitory effect on A20 cells, which may be attributed to the consumption of GSH and the production of ·OH by the Fenton-like reaction. In addition, at the same concentration, the cell survival rate of the CM@HFeS / DOX / MSA-2 group was significantly lower than that of the CM@HFeS group and CM@HFeS / DOX. This may be attributed to the synergistic effect of GSH consumption, ROS generation, hypoxia relief and CDDP release under the precise response of TME, further synergistically activating the cGAS-STING pathway and ferroptosis. This also shows that the drug delivery system constructed in the embodiment of the present invention can achieve better therapeutic effects.

[0083] The technical features of the above-described embodiments can be combined in any combination. To simplify the description, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification. It should be pointed out that for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent of this invention shall be based on the attached claims.

Claims

1. A lymphoma drug delivery system, characterized in that: The hollow iron-based nanozyme is used as the core carrier, loaded with the chemotherapy drug DOX and the STING signaling pathway agonist MSA-2, and coated with lymphoma cell membranes; The hollow iron-based nanozyme is prepared by the following method: Tetraethoxysilane, anhydrous ethanol, deionized water and ammonia water were stirred and reacted at room temperature to obtain nano-SiO2; The nano-SiO2 and trivalent soluble iron salt prepared above were dispersed in deionized water to obtain a mixed solution I. Subsequently, a NaBH4 aqueous solution was slowly added under stirring, and the final mixture was reacted at 70-90°C to obtain the hollow iron-based nanozyme HFeS.

2. The lymphoma drug delivery system according to claim 1, characterized in that According to the volume ratio, tetraethoxysilane: anhydrous ethanol: deionized water: ammonia water = 1.0-2.0: 20-30: 1.5-3: 0.3-0.6, the reaction time is 12-16 hours, and the ammonia water is 25-28% ammonia water.

3. The lymphoma drug delivery system according to claim 1, characterized in that In the mixed solution I, the SiO2 content is 0.3-10 mg / mL, Fe 3+ The content is 0.0015-0.0075mmol; The concentration of the NaBH4 aqueous solution is 110-240 mg / mL, According to the volume ratio, the mixed solution I: NaBH4 aqueous solution = 20-30: 2.5-3.5, and the reaction time is 6-10h.

4. Use of the lymphoma drug delivery system according to any one of claims 1 to 3 in the preparation of anti-tumor drugs.

5. The method for preparing the lymphoma drug delivery system according to any one of claims 1 to 3, wherein: Including steps: (1) Preparation of HFeS / DOX-loaded nanozymes: The chemotherapy drug DOX dispersion was added dropwise to the HFeS dispersion and stirred at room temperature to obtain the drug-loaded nanozyme HFeS / DOX. (2) Preparation of HFeS / DOX / MSA-2 drug-loaded nanozymes: HFeS / DOX and MSA-2 were dispersed in acetone, and the mixture was stirred at room temperature until 2 / 3 of the solvent evaporated, and then washed with ultrapure water to obtain HFeS / DOX / MSA-2; (3) Preparation of cell membrane-modified drug-loaded nanozyme CM@HFeS / DOX / MSA-2: The cancer cell membrane fragments were mixed with the HFeS / DOX / MSA-2 drug-loaded nanozymes prepared above, and CM@HFeS / DOX / MSA-2 was prepared by co-extrusion.

6. The preparation method according to claim 5, characterized in that In step (1), the concentration of the DOX dispersion is 3-7.5 mg / mL, the concentration of the HFeS dispersion is 1.5-2.5 mg / mL, and V DOX分散液 :V HFeS分散液 = 0.8-1.2: 8-12, stirring reaction time is 12-24h.

7. The preparation method according to claim 5, characterized in that In step (2), the weight ratio is HFeS / DOX:MSA-2 = 8-12:4-6.

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