Bionic MOF nano platform capable of dual-targeting cervical cancer tumor cells and cancer-related fibroblasts and co-delivering FAK inhibitor and bismuth as well as preparation method and application of bionic MOF nano platform

Abstract

The invention provides a bionic MOF nano platform capable of double targeting cervical cancer tumor cells and cancer-related fibroblasts and co-delivering an FAK inhibitor and bismuth as well as a preparation method and application thereof, the bionic MOF nano platform comprises an MOF material loaded with the FAK inhibitor (IN10018) and bismuth (Bi), and a hybrid membrane coating the outer part of the MOF material loaded with the FAK inhibitor and the bismuth, the hybrid membrane is obtained by mixing and physically extruding a cervical cancer tumor cell (HeLa and SiHa) membrane and a cancer-related fibroblast (CAFs) membrane. According to the bionic MOF nano platform, in an acid environment, the ZIF-8 nano particles loaded with the IN10018 and the Bi disintegrate, the IN10018 is released, CAFs infiltration in tumors is reduced, meanwhile, due to addition of the Bi, the radiation absorption efficiency is improved, and the sensitivity of the tumors to radiotherapy is further enhanced through a double-targeting mechanism.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedical materials, and in particular to a bionic MOF nano-platform 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 still relapse after radiotherapy, and the main reason for recurrence after radiotherapy is the tumor's own resistance. Therefore, developing strategies to improve radiosensitivity is crucial to improve patient prognosis. Radiotherapy (RT) uses ionizing radiation to eliminate local tumors, but its effectiveness is often hindered by physiological barriers within the tumor microenvironment, such as hypoxia, vascular abnormalities, and dense extracellular matrix. In the tumor microenvironment, CAFs play an important role by synthesizing extracellular matrix, thereby shaping the tumor microenvironment structure and profoundly affecting tumor progression and treatment outcomes. CAFs are considered to be the main contributors to radioresistance in various cancers, including lung cancer, esophageal cancer, gastrointestinal cancer, and breast cancer.

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

[0004] In view of the deficiencies of the above-mentioned prior art, 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 metal organic framework (MOF) nanoplatform, named IZB@CCM, is used to co-deliver FAK inhibitors and bismuth, aiming to improve the radiosensitivity of cervical cancer. ZIF-8 nanoparticles loaded with IN10018 and Bi are further wrapped by hybrid membranes derived from cancer-associated fibroblasts (CAFs) and cancer cells, thereby achieving precise targeting of these two types of cells. In an acidic environment, the nanoparticles disintegrate, release IN10018, reduce CAFs infiltration in tumors, and thus enhance radiosensitivity. At the same time, the addition of bismuth improves the radiation absorption efficiency, further enhancing the sensitivity of tumors 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, wherein the hybrid membrane is obtained by physically extruding a mixture of a cervical cancer tumor cell membrane and a CAFs membrane.

[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 through a filter, 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, and 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, and the resulting supernatant was collected. After centrifugation at 4°C, cervical cancer tumor cell membrane precipitates and cancer-associated fibroblast membrane precipitates were obtained, respectively. 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 calculated according to the protein concentration, and then extruded using an Avanti extruder. The polycarbonate membranes with pore sizes of 800nm, 400nm and 200nm are extruded 11 times to obtain a hybrid membrane.

[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 800nm, 400nm and 200nm polycarbonate membranes using an Avanti extruder to obtain IZB@CCM.

[0014] Application of the bionic MOF nano-platform in the preparation of targeted drugs against cervical cancer.

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

[0016] The biomimetic MOF nanoplatform of the present invention is used to synergistically deliver IN10018 and Bi to improve the radiosensitivity of cervical cancer by dual-targeting cervical cancer tumor cells and CAFs. IN10018 can inhibit the function of CAFs in tumors by inhibiting the FAK signaling pathway, thereby enhancing radiosensitivity. At the same time, Bi is a relatively inert, generally non-toxic material with superior radiosensitization properties, which is expected to improve the therapeutic effect of radiotherapy.

[0017] Compared with traditional synthetic nanoparticles, cell membrane-coated nanoparticles effectively retain the functional properties of natural cell membranes. In addition, 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 confer multiple functions, such as enhanced biocompatibility, improved targeting efficiency to cancer, and immune evasion. The drug-loaded ZIF-8 nanoparticles of the present invention are coated with hybrid membranes from CAFs and cancer cells, allowing them to evade immune clearance and precisely target these two cell types. This dual-targeting strategy is expected to overcome the radioresistance of cervical cancer, has the potential to advance precision oncology, and become a successful example of combining nanotechnology with targeted therapy to enhance the efficacy of radiotherapy and improve patient outcomes. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 It is a schematic diagram of the synthesis of the bionic MOF nanoplatform IZB@CCM of the present invention;

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

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

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

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

[0023] Figure 6 is the SDS-PAGE experiment picture 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] Fig. 9 The characteristic spectra of ZB, IN10018 and IZB@CCM were compared using FTIR spectroscopy;

[0027] Fig.10 is the XRD analysis diagram;

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

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

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

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

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

[0033] Fig.16 This is the result diagram of homologous targeting of ZB@CCM;

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

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

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

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

[0038] The present invention is further described below in conjunction with the accompanying drawings and specific embodiments.

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

[0040] (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, centrifuged at 1000 rpm for 5 minutes, and the precipitate was resuspended and plated for 1.5 hours. After discarding the supernatant, the cells were cultured in complete medium DMEM. Subsequent in vitro experimental studies used CAFs of passages 3-10. BALB / 3T3 clone A31 cells were stimulated with TGF-β1 (100 ng / mL) for 2 days to generate mouse-derived CAFs for in vivo experimental studies.

[0041] (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)2 was added and stirred at 700 r / min for 30 min to successfully encapsulate 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 3 times with deionized water. IZB was obtained by freeze drying.

[0042] (3) Preparation of hybrid membranes: In order to obtain tumor cell membranes and CAFs membranes, cervical cancer tumor cells (HeLa and SiHa) and CAFs were collected with a cell scraper, centrifuged at 600g for 5 minutes, and washed with PBS. Subsequently, the cells were treated with membrane protein extraction reagent A. Incubated on ice for 15 minutes. Centrifuged at 700g for 10 minutes, the resulting supernatant was collected, and the cell membrane precipitate was obtained by centrifugation at 14000g for 30 minutes at 4°C. In order to obtain a hybrid membrane of tumor cell membrane and CAFs membrane, the two cell membranes to be hybridized were mixed at a mass ratio of 1:1 calculated according to the protein concentration. Then, an Avanti extruder was used to extrude the polycarbonate membranes with pore sizes of 800nm, 400nm and 200nm, respectively, and extruded 11 times. The tumor cells were purchased cervical cancer tumor cell lines HeLa and SiHa.

[0043] (4) Preparation of IZB@CCM: The protein content of the obtained hybrid membrane was obtained by BCA protein quantification, and 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.

[0044] Synthesis method 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 10000 rpm for 5 min, and the product was washed 3 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. To the solution, 2 mL of Zn(NO3)2·6H2O (100 mg) and 2 mL of NaBH4 (60 mg) were added respectively. After mixing for 10 min, the reaction mixture was then centrifuged at 10000 rpm for 5 min, and the product was washed 3 times with deionized water. ZB was obtained by freeze drying.

[0045] Preparation of ZB@CCM: The hybrid membrane was mixed with ZB in a ratio of 2:1, and then 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.

[0046] Hybrid membrane colocalization experiment: Confocal laser scanning microscopy was used to evaluate the colocalization of the membranes. 2.5 μL of DiO dye was added to 1 mL of the solution containing tumor cell membranes, and 2.5 μL of DiI dye was added to 1 mL of the solution containing CAFs membranes. Before mixing, the samples were washed three times with PBS to remove free DiO and DiI dyes, respectively. In order 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 hybrid membranes were obtained by centrifugation at 14,000 × g for 0.5 h at 4 °C and resuspended in PBS.

[0047] 5 μL of the hybrid membrane sample was placed on a glass slide. A physical mixture solution of DiO-labeled tumor cell membrane and DiI-labeled CAFs membrane was used as a control group.

[0048] Immunoblotting: Cells were lysed with RIPA buffer and total proteins were extracted. After determining the protein concentration, the samples were loaded into SDS-PAGE gel and electrophoresed. The proteins were then transferred to a PVDF membrane. The PVDF membrane was then blocked with 5% skim milk. Primary antibodies were used for overnight incubation at 4°C. The next day, the membrane was incubated with appropriate secondary antibodies for detection.

[0049] Lysosomal escape experiment: HeLa and SiHa cells were seeded into confocal cell culture dishes and cultured overnight to allow the cells to adhere. The cells were then incubated with Cy5-labeled IZB@CCM for 3 and 8 hours. Afterwards, they were washed three times with PBS to remove free nanoparticles and then stained with Lyso-Tracker green for 1 hour. Finally, after washing three times with PBS, the cell nuclei were stained with Hoechst33342.

[0050] Cell uptake experiment: HeLa, SiHa, MC38 and CAFs cells were seeded into confocal cell culture dishes and cultured overnight to allow the cells to adhere. The cells were then incubated with Cy5-labeled IZB@CCM for 6 h. After washing three times with PBS to remove free nanoparticles, the cell nuclei were stained with Hoechst 33342.

[0051] Cloning assay: Cervical cancer cells were seeded in 6-well plates, and then CAFs were co-cultured with cervical cancer cells for 24 hours. 24 hours before radiotherapy, the co-culture system was treated with IN10018 (5μM), ZB@CCM (5μM) and IZB@CCM (5μM) 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.

[0052] Immunofluorescence experiment: Cervical cancer cells were seeded into cell slides in 24-well plates and cultured overnight to allow cells to adhere. Then, CAFs cells were co-cultured with cervical cancer cells for 24 hours. Before exposure to 4Gy radiation, the co-culture system was treated with IN10018 (5μM), ZB@CCM (5μM) and IZB@CCM (5μM) for 24 hours. After 24 hours of radiotherapy, the cells were fixed with 4% paraformaldehyde and washed three times with PBS to remove free samples. Then, the cells were permeabilized with 0.5% Triton X-100 and blocked with 5% BSA. The primary anti-γ-H2AX antibody was used for incubation overnight at ℃. After incubation with the secondary antibody the next day, the cells were stained with DAPI.

[0053] In vivo distribution 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 collected. 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.

[0054] 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 100mm 3 Mice were treated with IN10018 (6.25 mg / kg, once daily, intravenous injection), ZB@CCM (6.25 mg / kg, once daily, intravenous injection), and IZB@CCM (6.25 mg / kg, once daily, intravenous injection) at 4 Gy of radiotherapy on the second day after the first drug treatment. Tumor volume and weight were measured every 2 days. The tumor volume was calculated as V = (long diameter × short diameter) 2 )×0.5.

[0055] The relevant experimental results are shown in the attached figure. Figure 2 Hybrid membranes (hybrid HCM and hybrid SCM) showed co-localization of green and red fluorescence signals. In contrast, physically mixed cell membranes (mixture HCM and mixture SCM) showed separate green and red fluorescence signals, indicating that the cell 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 the hybrid membrane HCM (or hybrid membrane SCM) simultaneously obtained proteins on the tumor cell membrane and the CAFs membrane. Figure 7The sizes of ZIF-8, ZB and IZB@CCM are 150.94 nm, 162.80 nm and 204.25 nm, respectively. Fig. 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. Fig.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. Fig.11 There are two obvious peaks at 275nm and 320nm. Fig.12 The linear fitting of the UV-visible absorption intensity at 320 nm and the concentration of IN10018 showed an obvious linear correlation. Fig.13 It was shown that IZB had an obvious characteristic peak at 320 nm, confirming the successful loading of IN10018. Fig.15 It shows that the release amount of IN10018 under weakly acidic environment is almost 5.2 times that under neutral conditions, indicating that the acidic degradation characteristics of ZIF-8 and the hybrid membrane do not affect the release amount of the drug. Fig.16 It indicates that ZB@CCM successfully achieved lysosomal escape and homologous targeting: Timely and effective lysosomal escape of nanoparticles is crucial to maintain the pharmacological activity of endocytosed drugs. At 3h, Cy5-labeled IZB@CCM co-localized with lysosomes, while at 8h, partial dissociation from lysosomes was observed, indicating successful lysosomal escape; Cy5-labeled IZB@CCM was selectively absorbed by HeLa (or SiHa) cells and CAFs, and the red fluorescence in these cells was significantly brighter compared with MC38 cells. These results show that IZB@CCM retains the characteristics from the cell membranes of HeLa (or SiHa) and CAFs and has homologous targeting. Fig.18 The results showed that IZB@CCM enhanced the radiosensitivity of cervical cancer cells in the co-culture system, and the number of tumor cell colonies in the IZB@CCM-treated group was significantly reduced compared with the other treatment groups. In addition, the γ-H2AX lesion formation experiment performed 24 hours after radiotherapy showed that the proportion of γ-H2AX lesions in the IZB@CCM group was significantly increased, indicating increased DNA damage. These results confirmed that IZB@CCM effectively improved the radiosensitivity of cervical cancer cells in the co-culture system. Fig.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 inhibition. However, the IZB@CCM+RT group showed the most significant tumor growth inhibition. Fig. 20 The results showed that IZB@CCM reduced the infiltration of CAFs in the tumor, thereby further improving the radiosensitivity of cervical cancer. IN10018 suppressed the level of p-FAK, while IZB@CCM had a greater inhibitory effect on p-FAK levels. In addition, the expression of α-SMA was lower in the IZB@CCM group compared with the IN10018 group, indicating that IZB@CCM had a stronger ability to reduce the expression of α-SMA. There was no significant difference in Ki67 staining among the different treatment groups, indicating that IN10018, ZB@CCM, and IZB@CCM did not enhance radiosensitivity by directly inhibiting tumor proliferation.

[0056] The above experimental results prove that the IZB@CCM obtained by the present invention can release IN10018, reduce CAFs infiltration in tumors, and thus enhance radiosensitivity. At the same time, the addition of bismuth improves the radiation absorption efficiency, further enhancing the sensitivity of tumors to radiotherapy.

[0057] Although 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 the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A biomimetic MOF nanoplatform that can dual-target cervical cancer tumor cells and cancer-associated fibroblasts and co-deliver FAK inhibitors and bismuth, characterized in that: 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 mixing a cervical cancer tumor cell membrane and a cancer-associated fibroblast cell membrane and then physically extruding the mixture.

2. A biomimetic MOF nanoplatform capable of dual-targeting cervical cancer tumor cells and cancer-associated fibroblasts and co-delivering FAK inhibitors and bismuth according to claim 1, characterized in that: The FAK inhibitor is IN10018.

3. 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, characterized in that: The steps include: (1) Extraction of cancer-associated fibroblasts: mince the tumor tissue sample, digest it with collagenase I, filter it through a cell suspension filter, centrifuge it, 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, and Zn(NO3)2 was added and stirred to completely encapsulate the drug. NaBH4 was added and reacted sufficiently, and the reaction mixture was centrifuged. The product was then washed with deionized water and freeze-dried to obtain IN10018 / Bi@ZIF-8. (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, and the resulting supernatant was collected. After centrifugation at 4°C, cervical cancer tumor cell membrane precipitates and cancer-associated fibroblast membrane precipitates were obtained, respectively. 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.

4. The method for preparing a biomimetic MOF nanoplatform capable of dual-targeting cervical cancer tumor cells and cancer-associated fibroblasts and co-delivering FAK inhibitors and bismuth according to claim 3, 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 800nm, 400nm and 200nm are extruded 11 times to obtain a hybrid membrane.

5. The method for preparing a biomimetic MOF nanoplatform capable of dual-targeting cervical cancer tumor cells and cancer-associated fibroblasts and co-delivering FAK inhibitors and bismuth according to claim 3, characterized in that: In the step (4), the obtained hybrid membrane is mixed with IN10018 / Bi@ZIF-8 at a mass ratio of 2:1, and the mixed solution is extruded 11 times through 800nm, 400nm and 200nm polycarbonate membranes using an Avanti extruder to obtain IZB@CCM.

6. Use of the bionic MOF nanoplatform according to any one of claims 1 to 5 in the preparation of targeted drugs against cervical cancer.

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