Biomimetic MOF nanoplatform for dual-targeted co-delivery of FAK inhibitor and bismuth to enhance cervical cancer radiosensitivity

Abstract

Radiation therapy (RT) remains the primary treatment modality for advanced cervical cancer, however, recurrence due to radioresistance presents a significant challenge. Cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) are key contributors to this resistance, driven by their inherent radioresistance and radiation-induced phenotypic adaptations. Addressing this issue requires strategies specifically designed to target CAFs and enhance their radiosensitivity. In this study, we developed a biomimetic metal–organic framework (MOF) nanoplatform for the dual-targeted co-delivery of the FAK inhibitor IN10018 and Bismuth (Bi), aimed at improving radiosensitivity in cervical cancer. The IN10018 and Bi-loaded zeolitic imidazolate framework 8 (ZIF-8) nanoparticles (IZB) were further coated with hybrid membranes derived from CAFs and cancer cells, enabling precise targeting of both cell types. Upon exposure to an acidic environment, the nanoparticles disassemble, releasing IN10018, which reduces CAFs infiltration and enhances radiosensitivity. Simultaneously, the incorporation of Bi enhances radiation absorption efficiency, further sensitizing tumor cells to radiotherapy. This dual-target strategy represents a promising approach to overcoming radioresistance in cervical cancer and exemplifies how integrating nanotechnology with targeted therapies can enhance RT efficacy and improve patient outcomes. Schematic Illustration of IZB@CCM Construction and Application for Cervical Cancer to Improve Radiosensitivity. (1) IZB was fabricated through the one-pot method. (2) Preparation of hybrid CAF-cancer cell membrane. (3) IZB@CCM were obtained by co-extrusion of IZB and hybrid membrane (CCM). (4) IZB@CCM demonstrated the ability to target CAFs and cancer cells. (5) IZB@CCM inhibited the expression of FAK and released radiosensitizer Bi to enhance the radiosensitivity of cervical cancer.