Hollow iron-based nano-enzyme, drug delivery system and preparation method and application of hollow iron-based nano-enzyme

Abstract

The invention relates to a hollow iron-based nano-enzyme, a drug delivery system and a preparation method and application of the hollow iron-based nano-enzyme. The hollow iron-based nano-enzyme is prepared by the following steps: stirring tetraethoxysilane, absolute ethyl alcohol, deionized water and ammonia water at room temperature for reaction to obtain nano SiO2; the preparation method comprises the following steps: firstly, dispersing nano SiO2 and a trivalent soluble ferric salt in deionized water to obtain a mixed solution I, then slowly adding a NaBH4 aqueous solution while stirring, and finally, reacting the mixture at 70-90 DEG C to obtain the composite material. The hollow iron-based nano-enzyme can better consume GSH and load drugs, a drug delivery system is designed on the basis of the hollow iron-based nano-enzyme, and anti-tumor immune response is remarkably enhanced through synergistic activation of ferroptosis and cGAS-STING pathways.

Description

Technical Field

[0001] The present invention belongs to the field of medical materials, and particularly relates to a hollow iron-based nanozyme, a drug delivery system, and their preparation methods and applications. Background Art

[0002] Lymphoma is one of the malignant tumors with a relatively high incidence globally. Although traditional chemotherapy and radiotherapy methods have achieved certain therapeutic effects, in advanced or widely metastatic cases, their efficacy is often limited. This is mainly attributed to the immunosuppressive characteristics of the tumor microenvironment (TME), as well as the tolerance and escape mechanisms of tumor cells to treatment. This immunosuppressive TME usually shows insufficient tumor-infiltrating lymphocytes (TILs), excessive accumulation of immunosuppressive cells (such as myeloid-derived suppressor cells and regulatory T cells), and low antigen presentation efficiency, thus significantly weakening the anti-tumor immune response. In recent years, developing new strategies that can effectively reshape the TME and stimulate a persistent anti-tumor immune response has become one of the important directions in tumor immunotherapy.

[0003] As an important pathway of innate immunity, the cyclic guanosine monophosphate-adenosine monophosphate synthase stimulator (cGAS-STING) signaling pathway induces the production of type I interferon (IFN-I) and pro-inflammatory cytokines by recognizing double-stranded DNA (dsDNA) in the cytoplasm, thereby activating adaptive immunity. This pathway can not only effectively activate dendritic cells (DCs), but also stimulate the infiltration of cytotoxic T lymphocytes (CTLs) into the tumor site, enhancing the anti-tumor immune response. However, in tumor treatment, the activation of the cGAS-STING pathway still faces many challenges: firstly, the release of dsDNA in the cytoplasm is often insufficient, unable to provide enough signaling molecules to effectively activate cGAS; secondly, the sensitivity of cGAS to dsDNA binding is low, resulting in low activation efficiency of the pathway. High concentrations of GSH and the hypoxic environment also inhibit the immune activation process triggered by treatment.

[0004] In addition, tumor cells often inhibit the continuous activation of the pathway by increasing the glutathione (GSH) level or enhancing the DNA repair ability. These limitations indicate that it may be difficult to fully stimulate the anti-tumor immune response only by activating the cGAS-STING pathway.

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

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

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

[0008] To overcome the above obstacles, in this study, a novel intelligent drug delivery system (DDS) was developed based on a hollow iron-based nanozyme synthesized by a simple method. This system can effectively induce ferroptosis and activate the cGAS-STING pathway, enabling precise immune regulation of tumors.

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

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

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

[0012] The prepared nano-SiO 2 and trivalent soluble iron salt are dispersed in deionized water to obtain a mixed solution I. Subsequently, an aqueous solution of NaBH 4 is slowly added under stirring, and the final mixture is reacted at 70-90 °C to obtain the hollow iron-based nanozyme HFeS.

[0013] The obtained hollow iron-based nanozyme HFeS has excellent peroxidase (POD)-like and Fenton catalytic activities. In the TME, HFeS can react with high levels of GSH, consume GSH and generate a large amount of Fe2+, thereby producing hydroxyl radicals (·OH) through the Fenton reaction and inducing ferroptosis. In addition, hydroxyl radicals and oxidative stress can trigger the release of mitochondrial DNA and damage nuclear DNA at the same time, thereby further activating the cGAS-STING pathway. It can consume GSH, relieve the antioxidant and immunosuppressive properties of the TME. Regulate redox homeostasis, reduce the immunosuppressive state of tumor tissues, promote the infiltration and activation of immune cells, and improve the tumor microenvironment. Moreover, the hollow nanozyme is also beneficial for drug loading.

[0014] In a preferred embodiment, by volume, tetraethoxysilane: absolute ethanol: deionized water: ammonia water = 1.0 - 2.0: 20–30: 1.5 - 3: 0.3 - 0.6, the reaction time is 12 - 16 h, and the ammonia water is 25–28% ammonia water.

[0015] In a preferred embodiment, in the mixed solution I, the content of SiO 2 is 0.3 - 10 mg / mL, and the content of Fe3+ is 0.0015 - 0.0075 mmol; the concentration of the NaBH 4 aqueous solution is 110 - 240 mg / mL; by volume, mixed solution I: NaBH 4 aqueous solution = 20 - 30: 2.5 - 3.5, and the reaction time is 6 - 10 h.

[0016] In a second aspect of the present invention, there is provided the use of the hollow iron-based nanozyme in the preparation of anti-tumor drugs.

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

[0018] The tumor cell membrane coating technology can endow the nano-carrier with the ability of "camouflage", and use the homologous adhesion molecules on the membrane surface to achieve precise delivery to tumor tissues. At the same time, the cell membrane can effectively avoid the recognition of the immune system, prolong the circulation time of the nano-carrier in the body, and improve the drug delivery efficiency.

[0019] In the fourth aspect of the present invention, there is provided the use of the described drug delivery system in the preparation of anti-tumor drugs.

[0020] In the fifth aspect of the present invention, there is provided a drug delivery system for lymphoma, using the described hollow iron-based nanozyme as the core carrier, loaded with the chemotherapeutic drug DOX and the STING signaling pathway agonist MSA-2, and coated with lymphoma cell membranes.

[0021] In the sixth aspect of the present invention, there is provided a preparation method of the described drug delivery system for lymphoma, including the steps:

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

[0023] Dropwise add the chemotherapeutic drug DOX dispersion into the HFeS dispersion, and stir and react at room temperature to obtain the drug-loaded nanozyme HFeS / DOX;

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

[0025] Disperse HFeS / DOX and MSA-2 in acetone, stir the mixture at room temperature until 2 / 3 of the solvent evaporates, and then wash 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] Mix the cancer cell membrane fragments with the HFeS / DOX / MSA-2 drug-loaded nanozyme prepared above, and prepare CM@HFeS / DOX / MSA-2 by the co-extrusion method.

[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, V DOX分散液 :V HFeS分散液 = 0.8 - 1.2:8 - 12, and the stirring reaction time is 12 - 24 h.

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

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

[0031] Compared with the prior art, based on the synthesized hollow iron-based nanozyme HFeS, the present invention designs an intelligent drug delivery system with HFeS as the core, which significantly enhances the anti-tumor immune response through the synergistic activation of ferroptosis and the cGAS-STING pathway. This system not only has unique advantages in improving the tumor microenvironment and promoting immune cell infiltration, but also provides a solution with potential clinical transformation value for the precise treatment of systemic lymphoma through multifunctional synergistic effects. Description of the Drawings

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

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

[0034] Figure 3 is the flow cytometry histogram (A) of treating HUVEC, L929, MB49 and A20 cells with CM@HFeS / DOX / MSA-2; the fluorescence quantitative bar chart (B) in different cells;

[0035] Figure 4 is the cytotoxicity of different concentrations of CM@HFeS to L929 (A); the cytotoxicity of CM@HFeS, CM@HFeS / DOX and CM@HFeS / DOX / MSA-2 to A20 (B). Detailed Embodiments

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

[0037] Tetraethoxysilane, absolute ethanol, deionized water and ammonia water are stirred and reacted at room temperature to obtain spherical nano-SiO 2 ;

[0038] The above-prepared spherical nano-SiO 2 and trivalent soluble iron salt are dispersed in deionized water to obtain a mixed solution I. Subsequently, an aqueous solution of NaBH 4 is slowly added under stirring, and the final mixture is reacted at 70-90 °C to obtain the hollow iron-based nanozyme HFeS.

[0039] The present invention etches spherical nano-SiO 2 with trivalent iron to form a hollow structure, providing a higher specific surface area and drug loading efficiency, and significantly increasing the treatment dose. HFeS is controllably degraded in the acidic environment of the TME to release Fe2 +Precisely induce ferroptosis and avoid damage to normal tissues caused by excessive ROS production. Compared with traditional nanozymes, the HFeS of the present invention combines high-efficiency drug loading and TME-responsive characteristics and is the core for subsequent design of multifunctional nano-therapeutic platforms.

[0040] Meanwhile, based on this hollow iron-based nanozyme, the present invention designs a drug delivery system. Using the above-mentioned hollow iron-based nanozyme as the core carrier, it is loaded with chemotherapeutic drugs and STING signaling pathway agonists and coated with tumor cell membranes. The chemotherapeutic drugs increase the level of cytoplasmic dsDNA through nuclear DNA damage, and the STING signaling pathway agonists enhance the immune response by directly activating the STING signal, and can synergistically increase the level of cytoplasmic dsDNA with the hollow iron-based nanozyme core carrier to activate the STING signal.

[0041] This drug delivery system combines the dual effects of chemotherapy and immunotherapy through the co-presence of chemotherapeutic drugs and STING signaling pathway agonists. ROS is generated through the Fenton reaction of the nanozyme to further enhance the ICD effect induced by DOX and provide a stronger initial stimulation signal for immunotherapy. The release of MSA-2 is precisely controlled by TME conditions to ensure its immune activation effect at the tumor site rather than systemic distribution and side effects, thus overcoming the deficiencies in existing combined chemotherapy and immunotherapy strategies where drug carriers usually only deliver chemotherapeutic drugs or immune activators singly and lack an effective co-therapeutic design. The efficacy of some immune activators is limited by their delivery efficiency and it is difficult to produce a high-efficiency immune stimulus at the tumor site.

[0042] Moreover, HFeS can achieve precise drug release through weak acidity and high GSH level responses. The release rate of the load is regulated according to TME to ensure the effective concentration of the drug in the tumor area while reducing damage to normal tissues.

[0043] Meanwhile, the coating of tumor cell membranes can utilize the specific targeting effect of membrane proteins to achieve precise recognition and drug delivery to tumors. In addition, membrane modification can also effectively avoid the recognition of the host immune system and improve the drug delivery efficiency. Thereby, it can overcome the deficiencies that the targeting of existing drug delivery systems generally relies on chemical modification or antibody coupling, and these methods are easily cleared by the host immune system, resulting in low targeting efficiency.

[0044] Moreover, the coating of tumor cell membranes in the present invention can improve the affinity of the drug-loading system for tumor tissues and enhance the ability to escape the immune system, significantly improving the enrichment efficiency of the drug at the tumor site. Compared with traditional chemical targeting strategies, the 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 the core carrier, loaded with the chemotherapeutic drug DOX and the STING signaling pathway agonist MSA-2, and coated with lymphoma cell membranes.

[0046] In summary, in order to overcome the deficiencies of the prior art in terms of drug delivery efficiency, immune activation, and targeting accuracy. The present invention constructs a multifunctional nanocarrier, combines the synergistic mechanisms of chemotherapy, immunotherapy, and ferroptosis induction, adopts a comprehensive scheme of hollow structure design, combined drug loading, homologous targeting modification, and TME-responsive release, significantly improving the anti-tumor treatment effect and providing a new technical path for the multimodal combination treatment of tumors.

[0047] The following specific examples are used to further illustrate the present invention, 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 technical field. Unless otherwise specified, the reagents and materials used in the following examples are all commercially available. Example 1 Preparation of hollow iron-based nanozyme HFeS

[0048] (1) Preparation of SiO 2

[0049] Mix 1 mL of TEOS, 25 mL of absolute ethanol, 2 mL of deionized water, and 0.5 mL of 25-28% ammonia water and stir at room temperature for 14 h. Wash the white precipitate several times with absolute ethanol and deionized water, and then collect by centrifugation (8000 rpm, 10 min).

[0050] (2) Preparation of HFeS nanozyme

[0051] Dissolve 150 mg of SiO 2 and 0.10 mmol of FeCl 3 ·6H 2 O by ultrasound in 27 mL of deionized water. Subsequently, slowly add an aqueous solution of NaBH 4 (500 mg, 3 mL of ice-cold deionized water) to the above mixture under stirring. React the final mixture in a 20 mL reactor at 80 °C for 8 h, and then purify the product by three consecutive washing / centrifugation cycles (10,000 rpm) using absolute ethanol and deionized water.

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

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

[0054] ​Weigh 5 mg of DOX and dissolve it in 1 mL of pure water. Then, add it drop by drop to the above-mentioned 10 mL of 2 mg / mL HFeS nanozyme dispersion, stir overnight at room temperature, and wash it by centrifugation with water multiple times to obtain the drug-loaded nanozyme HFeS / DOX.

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

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

[0057] The encapsulation of the cell membrane is carried out by the extrusion method.

[0058] First, disperse the prepared cancer cell membrane fragments evenly in deionized water. Then, add HFeS / DOX / MSA-2, and use an Avanti liposome extruder to co-extrude the mixture of the cell membrane fragments and HFeS / DOX / MSA-2 through polycarbonate membranes with different pore sizes (1 μm, 0.8 μm, 0.45 μm) in sequence. Finally, centrifuge the extruded mixture at 8000 rpm for 10 minutes to collect CM@HFeS / DOX / MSA-2.

[0059] Comparative Example 1 Preparation of CM@HFeS

[0060] Refer to the method of Example 2, omit steps (1) and (2), and directly mix HFeS with the cell membrane fragments and prepare CM@HFeS by the extrusion method.

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

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

[0063] Test Example

[0064] (1) TEM Characterization

[0065] Figure 1 This is the transmission electron microscopy image 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 etching with ferric chloride for 8 h in Example 1 is a hollow iron-doped SiO 2 sphere. The generation of the hollow structure after etching may be based on the 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. Finally, the absorbance values of each group at 412 nm were immediately measured using a UV-visible spectrophotometer.

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

[0070] In summary, 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 by four types of cells, namely MB49, HUVEC, L929, and A20.

[0073] Specifically, 1×10 5 cells per well were cultured overnight for adhesion. CM@HFeS / DOX (0.5 mL, 50 μg / mL) was added to the cells and incubated for 4 h. Then, the original culture medium was aspirated, and the cells were washed 3 times with PBS, fixed with paraformaldehyde for 10 minutes, and stained with DAPI for 15 min. After incubation, the cells were washed 3 times with PBS and analyzed using a flow cytometer. As Figure 3 shown in A and B, the cancer cell membrane biomimetic camouflage strategy is beneficial for targeting, which in turn promotes the active uptake of the biomimetic camouflaged nano-drugs by homologous cancer cells. The uptake of CM@HFeS / DOX in each cell line was quantitatively analyzed using a flow cytometer. The average fluorescence intensity of homologous cells (A20) was approximately twice that of heterologous cells (such as MB49).

[0074] (2) Cytotoxicity

[0075] A. The cytotoxicity of CM@HFeS against L929 cells was evaluated using the method of detecting cell viability with CCK-8.

[0076] The specific operation steps are as follows: First, inoculate L929 cells into a 96-well plate at a density of 5000 cells / well, and then place it in a carbon dioxide incubator to culture and adhere overnight. Subsequently, aspirate the original medium and replace it with fresh complete medium containing different concentrations of CM@HFeS. The selected concentration range of CM@HFeS is 0 - 200 μg / mL, and there are 3 parallels for each concentration. Then culture in the incubator for 24 h. After culturing, wash the cells once with PBS and add 100 μL of fresh medium (containing 10% CCK-8) to each well. Incubate in the incubator for a period of time, and finally use an enzyme-linked immunosorbent assay (ELISA) reader to detect and record the absorbance at a wavelength of 450 nm. Calculate the cell survival rate through the following formula:

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

[0078] The results are as Figure 4 shown in A. After co-incubation with CM@HFeS for 24 hours, the activity of L929 cells remained above 80%, which can be attributed to the satisfactory biocompatibility of CM@HFeS.

[0079] B. Use the method of detecting cell activity by CCK-8 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, inoculate A20 cells into a 96-well plate at a density of 5000 cells / well, and then place it in a carbon dioxide incubator to culture and adhere overnight. Subsequently, aspirate the original medium and replace it with fresh complete medium containing the sample. Then culture in the incubator for 24 h. After culturing, wash the cells once with PBS and add 100 μL of fresh medium (containing 10% CCK-8) to each well. Incubate in the incubator for a period of time, and finally use an ELISA reader to detect and record the absorbance at a wavelength of 450 nm. Calculate the cell survival rate through the following formula:

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

[0082] The results are as Figure 4As shown in 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 generation of ·OH by the Fenton-like reaction. In addition, the cell viability of the CM@HFeS / DOX / MSA-2 group at the same concentration was significantly lower than that of the CM@HFeS group and CM@HFeS / DOX, which may be attributed to the synergistic effect of the consumption of GSH, the generation of ROS, the alleviation of hypoxia, and the precise response of the release of CDDP in the TME, further synergistically activating the cGAS-STING pathway and ferroptosis. This also indicates that the drug delivery system constructed in the embodiments of the present invention can achieve better therapeutic effects.

[0083] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered that the scope described in this specification. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the present invention patent shall be subject to the appended claims.

Claims

1. A hollow iron-based nanozyme, characterized in that: The hollow iron-based nanozyme is prepared by the following method: Tetraethoxysilane, anhydrous ethanol, deionized water and ammonia water are stirred and reacted at room temperature to obtain nano-SiO2; The nano-SiO2 and trivalent soluble iron salt prepared above are 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 to obtain the hollow iron-based nanozyme HFeS.

2. The hollow iron-based nanozyme 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 hollow iron-based nanozyme 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 hollow iron-based nanozyme as described in any one of claims 1 to 3 in the preparation of anti-tumor drugs.

5. A drug delivery system, characterized in that: The drug delivery system uses the hollow iron-based nanozyme described in any one of claims 1 to 3 as a core carrier, is loaded with chemotherapy drugs and STING signaling pathway agonists, and is coated with tumor cell membranes.

6. Use of the drug delivery system according to claim 5 in the preparation of anti-tumor drugs.

7. A lymphoma drug delivery system, characterized in that: The hollow iron-based nanozyme according to any one of claims 1 to 3 is used as a core carrier, loaded with the chemotherapy drug DOX and the STING signaling pathway agonist MSA-2, and coated with a lymphoma cell membrane.

8. The method for preparing the lymphoma drug delivery system according to claim 7, characterized in that: Includes steps: (1) Preparation of HFeS / DOX-loaded nanozymes: The chemotherapeutic drug DOX dispersion was added dropwise into the HFeS dispersion, and the mixture was 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.

9. The preparation method according to claim 8, 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.

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

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