A biomimetic MOF nanoplatform capable of dual-targeting cervical cancer tumor cells and cancer-associated fibroblasts and co-delivering FAK inhibitors and bismuth, as well as its preparation method and application

Abstract

The present invention provides a biomimetic MOF nanoplatform that can dual-target cervical cancer tumor cells and cancer-associated fibroblasts and co-deliver FAK inhibitors and bismuth, and its preparation method and application. The biomimetic MOF nanoplatform includes a MOF material loaded with FAK inhibitors (IN10018) and bismuth (Bi), and a hybrid membrane coated on the outside of the MOF material loaded with FAK inhibitors and bismuth. The hybrid membrane is obtained by physical extrusion after mixing cervical cancer tumor cell (HeLa and SiHa) membranes and cancer-associated fibroblast (CAFs) membranes. In an acidic environment, the biomimetic MOF nanoplatform of the present invention disintegrates ZIF-8 nanoparticles loaded with IN10018 and Bi, releases IN10018, reduces CAFs infiltration in the tumor, and at the same time, the addition of Bi improves radiation absorption efficiency, further enhancing the sensitivity of the tumor to radiotherapy through a dual-targeting mechanism.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedical materials, and in particular to a biomimetic MOF nanoplatform capable of dual-targeting cervical cancer tumor cells and cancer-associated fibroblasts and co-delivering a FAK inhibitor and bismuth, as well as a preparation method and application thereof. Background Art

[0002] Cervical cancer is the fourth most common malignancy among women worldwide. Radical concurrent chemoradiotherapy is the standard treatment for patients with advanced or locally advanced cervical cancer. However, approximately 30% of patients with advanced cervical cancer relapse after radiotherapy, primarily due to tumor resistance. Therefore, developing strategies to enhance radiosensitivity is crucial for improving patient outcomes. Radiotherapy (RT) uses ionizing radiation to eliminate localized tumors, but its effectiveness is often hampered by physiological barriers within the tumor microenvironment, such as hypoxia, vascular abnormalities, and a dense extracellular matrix. Within the tumor microenvironment, CAFs (cellular adenocarcinoma cells) play a crucial role by synthesizing the extracellular matrix, thereby shaping the tumor microenvironment and profoundly influencing tumor progression and treatment outcomes. CAFs are considered a major contributor to radioresistance in various cancers, including lung, esophageal, gastrointestinal, and breast cancers.

[0003] FAK is a non-receptor tyrosine kinase located at the site of cell-extracellular matrix adhesion. It receives signals from the extracellular matrix via integrins. ZIF-8, a commonly used MOF, is known for its stability and rapid degradation in low pH environments due to protonation, making it particularly effective for drug release under the acidic conditions typical of tumors. However, the synergistic combination of several substances or materials for tumor immunotherapy has not been studied. Summary of the Invention

[0004] To address the shortcomings of the aforementioned prior art, the present invention provides a biomimetic MOF nanoplatform capable of dual-targeting cervical cancer cells and cancer-associated fibroblasts (CAFs) and co-delivering a FAK inhibitor and bismuth, as well as its preparation method and application. This biomimetic metal-organic framework (MOF) nanoplatform, named IZB@CCM, is designed to co-deliver a FAK inhibitor and bismuth, aiming to enhance the radiosensitivity of cervical cancer. ZIF-8 nanoparticles loaded with IN10018 and Bi are further encapsulated by hybrid membranes derived from cancer-associated fibroblasts (CAFs) and cancer cells, enabling precise targeting of both cell types. In an acidic environment, the nanoparticles disintegrate, releasing IN10018, which reduces CAF infiltration in tumors and enhances radiosensitivity. Furthermore, the addition of bismuth improves radiation absorption efficiency, further enhancing the tumor's sensitivity to radiotherapy.

[0005] The technical solution provided by the present invention is: a bionic MOF nanoplatform that can dual-target cervical cancer tumor cells and cancer-associated fibroblasts and co-deliver FAK inhibitors and bismuth, including a MOF material loaded with FAK inhibitors and bismuth, and a hybrid membrane coated on the outside of the MOF material loaded with FAK inhibitors and bismuth. The hybrid membrane is obtained by physically extruding a mixture of cervical cancer tumor cell membranes and CAFs membranes.

[0006] Furthermore, the FAK inhibitor is IN10018.

[0007] Another technical solution provided by the present invention is a method for preparing a biomimetic MOF nanoplatform that can dual-target cervical cancer tumor cells and cancer-associated fibroblasts and co-deliver FAK inhibitors and bismuth, comprising the following steps:

[0008] (1) Extraction of cancer-associated fibroblasts (CAFs): mince the tumor tissue sample, digest it with collagenase I, filter the cell suspension, centrifuge, resuspend the precipitate and plate it, discard the supernatant, and culture the cells in complete medium DMEM;

[0009] (2) Synthesis of IN10018 / Bi@ZIF-8 (IZB): 2-Methylimidazole (2-MIM), IN10018, and Bi(NO3)3·5H2O were dissolved in deionized water. Zn(NO3)2 was added and stirred to completely encapsulate the drug. NaBH4 was added and the reaction mixture was centrifuged after sufficient reaction. The product was then washed with deionized water and freeze-dried to obtain IN10018 / Bi@ZIF-8.

[0010] (3) Preparation of hybrid membranes: Cervical cancer tumor cells and cancer-associated fibroblasts were collected using a cell scraper, washed with PBS after centrifugation, treated with a membrane protein extraction reagent, incubated on ice, and centrifuged. The supernatant was collected and centrifuged at 4°C to obtain cervical cancer tumor cell membrane precipitates and cancer-associated fibroblast membrane precipitates. The two cell membranes to be hybridized were mixed and then extruded separately using an Avanti extruder to obtain hybrid membranes.

[0011] (4) The obtained hybrid membrane was mixed with IN10018 / Bi@ZIF-8, and the mixed solution was extruded using an Avanti extruder to obtain IZB@CCM.

[0012] Furthermore, the two cell membranes to be hybridized in step (3) are mixed in a mass ratio of 1:1 according to the protein concentration, and then extruded using an Avanti extruder. The polycarbonate membranes with pore sizes of 800 nm, 400 nm and 200 nm are respectively extruded 11 times to obtain hybrid membranes.

[0013] Furthermore, the hybrid membrane obtained in step (4) was mixed with IN10018 / Bi@ZIF-8 at a mass ratio of 2:1, and the mixed solution was extruded 11 times through 800 nm, 400 nm and 200 nm polycarbonate membranes using an Avanti extruder to obtain IZB@CCM.

[0014] Application of the bionic MOF nanoplatform in the preparation of targeted drugs for treating cervical cancer.

[0015] The present invention improves the radiosensitivity of tumor cells by inhibiting FAK kinase activity using a FAK inhibitor. FAK inhibitors can reduce the deposition of CAFs. The FAK inhibitor IN10018 effectively inhibits FAK activity by inhibiting FAK phosphorylation. Unlike some other FAK inhibitors, it does not have off-target effects on its family analog PYK2.

[0016] The biomimetic MOF nanoplatform of this invention is used to synergistically deliver IN10018 and Bi, enhancing the radiosensitivity of cervical cancer by dually targeting cervical cancer cells and CAFs. IN10018 can inhibit the function of CAFs in tumors by inhibiting the FAK signaling pathway, thereby enhancing radiosensitivity. Furthermore, Bi is a relatively inert and generally non-toxic material with excellent radiosensitizing properties, potentially improving the therapeutic efficacy of radiotherapy.

[0017] Compared to traditional synthetic nanoparticles, cell membrane-coated nanoparticles effectively retain the functional properties of native cell membranes. Furthermore, hybrid membranes inherit the biological functions of different cell membranes by fusing cell membranes from different sources. Therefore, coating ZIF-8 nanoparticles with hybrid cell membranes can impart multiple functions, such as enhanced biocompatibility, improved cancer targeting efficiency, and immune evasion. The drug-loaded ZIF-8 nanoparticles of the present invention are coated with hybrid membranes derived from CAFs and cancer cells, enabling them to evade immune clearance and precisely target both cell types. This dual-targeting strategy has the potential to overcome radioresistance in cervical cancer, advance precision oncology, and become a successful example of combining nanotechnology with targeted therapy to enhance radiotherapy efficacy and improve patient outcomes. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 Schematic diagram of the synthesis of the biomimetic MOF nanoplatform IZB@CCM of the present invention;

[0019] Figure 2 This is a diagram of the hybrid membrane co-localization experiment of tumor cell membrane and CAFs membrane;

[0020] Figure 3 TEM images of ZIF-8, ZB, and IZB@CCM;

[0021] Figure 4 This is the element mapping image of zinc and Bi;

[0022] Figure 5 It is the EDS analysis diagram;

[0023] Figure 6 Figure 1 is the SDS-PAGE experiment of IZB@CM, IZB@HM, IZB@SM and IZB@CCM;

[0024] Figure 7 are the dimensions of ZIF-8, ZB, and IZB@CCM;

[0025] Figure 8 is the zeta potential of ZB, IN10018, IZB, and IZB@CCM;

[0026] Figure 9 The characteristic spectra of ZB, IN10018 and IZB@CCM were compared using FTIR spectroscopy;

[0027] Figure 10 is the XRD analysis diagram;

[0028] Figure 11 The UV-visible absorption spectra of IN10018 at different concentrations (10, 20, 20, and 40 μg / mL) were measured;

[0029] Figure 12 is a linear fitting graph of the UV-visible absorption intensity at 320 nm and the concentration of IN10018;

[0030] Figure 13 is the UV-visible spectra of IZB and ZB;

[0031] Figure 14 is the loading rate and encapsulation efficiency of IZB@CCM;

[0032] Figure 15 is the cumulative release rate of IN10018 at different pH values;

[0033] Figure 16 This is the result of homologous targeting of ZB@CCM;

[0034] Figure 17 IZB@CCM induced p-FAK degradation in a time- and dose-dependent manner;

[0035] Figure 18 is the radiosensitivity of cervical cancer cells in the co-culture system with IZB@CCM;

[0036] Figure 19is the radiosensitivity of IZB@CCM in cervical cancer in vivo;

[0037] Figure 20 IHC was used to detect p-FAK, Ki67 and α-SMA in Figure 19 Expression in tumors. DETAILED DESCRIPTION

[0038] The present invention will be further described below with reference to the accompanying drawings and specific embodiments.

[0039] A biomimetic MOF nanoplatform, named IZB@CCM, was developed for the co-delivery of FAK inhibitor IN10018 and Bi, targeting tumor cells and CAFs. Figure 1 Place

[0040] The following steps are included:

[0041] (1) Extraction of cancer-associated fibroblasts (CAFs): Tumor tissue samples were minced and digested with 0.1% collagenase I for 1 hour. The cell suspension was filtered through a 100 μm filter and centrifuged at 1000 rpm for 5 minutes. The pellet was resuspended and plated for 1.5 hours. After discarding the supernatant, the cells were cultured in complete DMEM medium. Subsequent in vitro studies used CAFs from passages 3 to 10. BALB / 3T3 clone A31 cells were stimulated with TGF-β1 (100 ng / mL) for 2 days to generate murine CAFs for in vivo studies.

[0042] (2) Synthesis of IN10018 / Bi@ZIF-8 (IZB): 2-MIM (1.94 g), IN10018 (15 mg), and Bi(NO3)3·5H2O (100 mg) were dissolved in 10 mL of deionized water. Then, 2 mL of Zn(NO3) was added and stirred at 2,700 rpm for 30 min to ensure complete encapsulation of the drug. Finally, 2 mL of NaBH4 (60 mg) was added and reacted for 10 min. The reaction mixture was then centrifuged at 10,000 rpm for 5 min, and the product was washed three times with deionized water. IZB was obtained by freeze drying.

[0043] (3) Preparation of hybrid membranes: To obtain tumor cell membranes and CAFs membranes, cervical cancer tumor cells (HeLa and SiHa) and CAFs were collected using a cell scraper, centrifuged at 600 g for 5 minutes, and washed with PBS. Subsequently, the cells were treated with membrane protein extraction reagent A. The cells were incubated on ice for 15 minutes. The supernatant was collected by centrifugation at 700 g for 10 minutes, and the cell membrane precipitate was obtained by centrifugation at 14,000 g for 30 minutes at 4°C. To obtain a hybrid membrane of tumor cell membranes and CAFs membranes, the two cell membranes to be hybridized were mixed at a mass ratio of 1:1 according to the protein concentration. Then, an Avanti extruder was used to extrude polycarbonate membranes with pore sizes of 800 nm, 400 nm, and 200 nm, respectively, for 11 times. The tumor cells were purchased cervical cancer tumor cell lines HeLa and SiHa.

[0044] (4) Preparation of IZB@CCM: The protein content of the obtained hybrid membrane was obtained by BCA protein quantification. The hybrid membrane was mixed with IZB at a mass ratio of 2:1. Subsequently, the mixed solution was extruded 11 times through 800 nm, 400 nm, and 200 nm polycarbonate membranes using an Avanti extruder to obtain IZB@CCM.

[0045] Synthesis of ZIF-8 and ZIF-8@Bi(ZB) used in the comparative example: 10 mL of 2-methylimidazole (2-MIM) (1.94 g) was quickly added to 0.5 mL of Zn(NO3)2 (100 mg) and stirred at 700 rpm for 10 min. The reaction mixture was then centrifuged at 10,000 rpm for 5 min, and the product was washed three times with deionized water. ZIF-8 was obtained by freeze drying. 2-MIM (1.94 g) and Bi(NO3)3·5H2O (100 mg) were dissolved in 10 mL of deionized water and stirred vigorously. 2 mL of Zn(NO3)2· 6H2O (100 mg) and 2 mL NaBH4 (60 mg) were added. After mixing for 10 min, the reaction mixture was centrifuged at 10,000 rpm for 5 min, and the product was washed three times with deionized water. ZB was obtained by freeze-drying.

[0046] Preparation of ZB@CCM: The hybrid membrane was mixed with ZB in a ratio of 2:1. Subsequently, the mixed solution was extruded 11 times through 800 nm, 400 nm, and 200 nm polycarbonate membranes using an Avanti extruder to obtain ZB@CCM.

[0047] Hybrid membrane colocalization assay: Membrane colocalization was assessed using confocal laser scanning microscopy. 2.5 µL of DiO dye was added to 1 mL of solution containing tumor cell membranes, and 2.5 µL of DiI dye was added to 1 mL of solution containing CAF membranes. Before mixing, the samples were washed three times with PBS to remove free DiO and DiI dye, respectively. To hybridize the two cell membranes, the mixed solution was extruded through 800 nm, 400 nm, and 200 nm polycarbonate porous membranes to prepare hybrid membranes. Finally, the mixture was centrifuged at 14,000 × g at 4°C for 0.5 h and resuspended in PBS to obtain the hybrid membranes.

[0048] 5µL of hybrid membrane sample was placed on a glass slide.

[0049] The physical mixture solution of DiI-labeled CAFs membrane served as the control group.

[0050] Western blotting: Cells were lysed with RIPA buffer and total protein was extracted. After determining protein concentration, the samples were loaded onto SDS-PAGE gels and subjected to electrophoresis. The proteins were then transferred to a PVDF membrane. The membrane was then blocked with 5% skim milk. Primary antibodies were then incubated overnight at 4°C. The next day, the membrane was incubated with an appropriate secondary antibody for detection.

[0051] Lysosomal escape assay: HeLa and SiHa cells were seeded onto confocal microplates and cultured overnight to allow attachment. The cells were then incubated with Cy5-labeled IZB@CCM for 3 and 8 hours. The cells were then washed three times with PBS to remove free nanoparticles and stained with Lyso-Tracker Green for 1 hour. Finally, after three washes with PBS, the cell nuclei were stained with Hoechst 33342.

[0052] Cell uptake experiment: HeLa, SiHa, MC38, and CAFs cells were seeded into confocal microplates and cultured overnight to allow the cells to adhere. The cells were then incubated with Cy5-labeled IZB@CCM for 6 hours. After washing three times with PBS to remove free nanoparticles, the cell nuclei were stained with Hoechst 33342.

[0053] Clonogenic assay: Cervical cancer cells were seeded in 6-well plates and then co-cultured with CAFs for 24 hours. Twenty-four hours before radiotherapy, the co-culture system was treated with IN10018 (5 μM), ZB@CCM (5 μM), and IZB@CCM (5 μM) for 24 hours. After 14-21 days, the cells were fixed with 4% paraformaldehyde for 60 minutes and then stained with 0.5% crystal violet solution for 2 hours.

[0054] Immunofluorescence assay: Cervical cancer cells were seeded onto cell slides in 24-well plates and cultured overnight to allow attachment. CAFs were then co-cultured with cervical cancer cells for 24 hours. Prior to exposure to 4 Gy of radiation, the co-culture system was treated with IN10018 (5 μM), ZB@CCM (5 μM), and IZB@CCM (5 μM), respectively, for 24 hours. Twenty-four hours after radiation treatment, cells were fixed with 4% paraformaldehyde and washed three times with PBS to remove free sample. Cells were then permeabilized with 0.5% Triton X-100 and blocked with 5% BSA. Primary anti-γ-H2AX antibodies were incubated overnight at 4°C. The following day, cells were incubated with secondary antibodies and stained with DAPI.

[0055] Biodistribution of IZB@CCM: To evaluate the biodistribution of IZB@CCM, mice bearing HeLa tumors were intravenously injected with 100 μL of 1 mg / mL Cy7-labeled IZB@CCM via the tail vein. Eight hours later, another mouse was euthanized, and tumor, heart, liver, spleen, lung, and kidney tissues were harvested. Fluorescence imaging was performed using a Bruker MI fluorescence imaging system with an excitation wavelength of 700 nm and an emission wavelength of 750 nm.

[0056] Animal experiment: 5-week-old female BALB / c nude mice were injected into the right axilla with 8 × 10 6 HeLa cells. When the average tumor volume reaches 100 mm 3 Mice were treated with IN10018 (6.25 mg / kg, once daily, intravenously), ZB@CCM (6.25 mg / kg, once daily, intravenously), and IZB@CCM (6.25 mg / kg, once daily, intravenously). 4 Gy of radiotherapy was given the day after the first drug treatment. Tumor volume and weight were measured every 2 days. Tumor volume was calculated as V = (longest diameter × shortest diameter) 2 )×0.5.

[0057] The relevant experimental results are shown in the attached figure. Figure 2 Hybrid membranes (hybrid HCM and hybrid SCM) exhibited colocalization of green and red fluorescence signals. In contrast, physically mixed membranes (mixture HCM and mixture SCM) showed separate green and red fluorescence signals, indicating that the membranes were not hybridized and fused. Figure 4 It was demonstrated that Bi successfully adhered to the surface of ZIF-8. Figure 5 It is proved that the ratio of Zn to Bi is 1:0.032. Figure 6 The results showed that hybrid membrane HCM (or hybrid membrane SCM) simultaneously obtained proteins on tumor cell membranes and CAFs membranes. Figure 7 The sizes of ZIF-8, ZB and IZB@CCM are 150.94 nm, 162.80 nm and 204.25 nm, respectively. Figure 9 IN10018 and IZB at 1721cm −1 、1680cm −1 and 1660cm −1 There is an obvious characteristic peak at 1350 -1 -1100cm −1 There are a large number of characteristic peaks at the same location. The presence of the same characteristic peaks indicates the successful loading of the drug. Figure 10 It was confirmed that IZB@CCM possessed Bi (27.7°, 37.1°, 39.6°) and ZIF-8 (6.97°, 10.4°, 12.6°, 16.3°, and 18.0°), showing the structural integrity of IZB@CCM. Figure 11 There are two obvious peaks at 275 nm and 320 nm. Figure 12 The linear fitting of the UV-visible absorption intensity at 320 nm and the concentration of IN10018 showed an obvious linear correlation. Figure 13 It was shown that IZB had an obvious characteristic peak at 320 nm, confirming the successful loading of IN10018. Figure 15 The release amount of IN10018 under weakly acidic conditions was almost 5.2 times that under neutral conditions, indicating that the acidic degradation characteristics of ZIF-8 and the hybrid membrane did not affect the release amount of the drug. Figure 16 This indicates that ZB@CCM successfully achieved lysosomal escape and homologous targeting: Timely and effective lysosomal escape of nanoparticles is crucial for maintaining the pharmacological activity of endocytosed drugs. At 3 hours, Cy5-labeled IZB@CCM colocalized with lysosomes, while at 8 hours, partial dissociation from lysosomes was observed, indicating successful lysosomal escape. Cy5-labeled IZB@CCM was selectively taken up by HeLa (or SiHa) cells and CAFs, and the red fluorescence in these cells was significantly brighter compared to MC38 cells. These results indicate that IZB@CCM retains properties derived from the HeLa (or SiHa) and CAFs cell membranes and has homologous targeting. Figure 18 The results showed that IZB@CCM enhanced the radiosensitivity of cervical cancer cells in the co-culture system. Compared with the other treatment groups, the IZB@CCM-treated group had significantly fewer tumor cell colonies. Furthermore, a γ-H2AX foci formation assay performed 24 hours after radiotherapy showed a significant increase in the proportion of γ-H2AX foci in the IZB@CCM group, indicating increased DNA damage. These results confirm that IZB@CCM effectively enhances the radiosensitivity of cervical cancer cells in the co-culture system. Figure 19The results showed that IZB@CCM enhanced the radiosensitivity of cervical cancer in vivo. Compared with the control group, the ZB@CCM group had no significant inhibitory effect on tumor growth. In contrast, the ZB@CCM+RT group showed partial tumor suppression. However, the IZB@CCM+RT group showed the most significant tumor growth inhibition. Figure 20 Results showed that IZB@CCM reduced CAF infiltration in tumors, further enhancing the radiosensitivity of cervical cancer. IN10018 suppressed p-FAK levels, with IZB@CCM having a greater inhibitory effect on p-FAK levels. Furthermore, α-SMA expression was lower in the IZB@CCM group compared to the IN10018 group, indicating that IZB@CCM was more capable of reducing α-SMA expression. There were no significant differences in Ki67 staining among the different treatment groups, indicating that neither IN10018, ZB@CCM, nor IZB@CCM enhanced radiosensitivity by directly inhibiting tumor proliferation.

[0058] The experimental results above demonstrate that the IZB@CCM obtained in this invention can release IN10018, reducing CAF infiltration in tumors, thereby enhancing radiosensitivity. Furthermore, the addition of bismuth improves radiation absorption efficiency, further enhancing tumor sensitivity to radiotherapy.

[0059] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A biomimetic MOF nanoplatform that can dual-target cervical cancer cells and cancer-associated fibroblasts and co-deliver FAK inhibitors and bismuth, characterized by: The invention comprises a MOF material loaded with a FAK inhibitor and bismuth, and a hybrid membrane coated on the outside of the MOF material loaded with a FAK inhibitor and bismuth. The hybrid membrane is obtained by physically extruding a mixture of a cervical cancer tumor cell membrane and a cancer-associated fibroblast cell membrane. The MOF material is ZIF-8, and the FAK inhibitor is IN10018.

2. A method for preparing a biomimetic MOF nanoplatform that can dual-target cervical cancer cells and cancer-associated fibroblasts and co-deliver FAK inhibitors and bismuth, characterized in that: The steps include: (1) Extraction of cancer-associated fibroblasts: mince the tumor tissue sample, digest it with collagenase I, filter the cell suspension, centrifuge, resuspend the precipitate and plate it, discard the supernatant, and culture the cells in complete medium DMEM; (2) Synthesis of IN10018 / Bi@ZIF-8: 2-Methylimidazole, IN10018, and Bi(NO3)3·5H2O were dissolved in deionized water. Zn(NO3)2 was added and stirred to completely encapsulate the drug. NaBH4 was added and reacted sufficiently. The reaction mixture was centrifuged and the product was washed with deionized water. IN10018 / Bi@ZIF-8 was obtained by freeze-drying. (3) Preparation of hybrid membranes: Cervical cancer tumor cells and cancer-associated fibroblasts were collected using a cell scraper, washed with PBS after centrifugation, treated with a membrane protein extraction reagent, incubated on ice, and centrifuged. The supernatant was collected and centrifuged at 4°C to obtain cervical cancer tumor cell membrane precipitates and cancer-associated fibroblast membrane precipitates. The two cell membranes to be hybridized were mixed and then extruded using an Avanti extruder to obtain a hybrid membrane. (4) The obtained hybrid membrane was mixed with IN10018 / Bi@ZIF-8, and the mixed solution was extruded using an Avanti extruder to obtain IZB@CCM.

3. The method for preparing a biomimetic MOF nanoplatform capable of dual-targeting cervical cancer cells and cancer-associated fibroblasts and co-delivering FAK inhibitors and bismuth according to claim 2, characterized in that: In the step (3), the two cell membranes to be hybridized are mixed in a mass ratio of 1:1 according to the protein concentration, and then extruded using an Avanti extruder. The polycarbonate membranes with pore sizes of 800 nm, 400 nm and 200 nm are respectively extruded 11 times to obtain hybrid membranes.

4. The method for preparing a biomimetic MOF nanoplatform capable of dual-targeting cervical cancer cells and cancer-associated fibroblasts and co-delivering FAK inhibitors and bismuth according to claim 2, characterized in that: The hybrid membrane obtained in step (4) was mixed with IN10018 / Bi@ZIF-8 at a mass ratio of 2:1, and the mixed solution was extruded 11 times through 800 nm, 400 nm and 200 nm polycarbonate membranes using an Avanti extruder to obtain IZB@CCM.

5. Use of the biomimetic MOF nanoplatform according to claim 1 or the biomimetic MOF nanoplatform prepared by any one of claims 2 to 4 in the preparation of targeted drugs for treating cervical cancer.

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