pH-Responsive bimetallic MOF nanoparticles enable triple-synergistic radiosensitization for enhanced radiotherapy

Radiotherapy (RT) faces hypoxia-induced radioresistance, as oxygen-deficient tumor regions limit reactive oxygen species (ROS) generation. Current hypoxia-targeting strategies (e.g., prodrugs, nanocarriers) struggle with inefficient delivery, off-target effects, and clinical translation barriers, necessitating advanced oxygenation or hypoxia-specific radiosensitization approaches. Herein, we developed pH-responsive BM-DOX@BSA nanoparticles (NPs) using a solvothermal method. Bi(NO₃)₃, MnCl₂, and TCPP were used as precursors, with DOX loaded for chemotherapy. BSA was added to enhance biocompatibility. In vitro and in vivo experiments assessed ROS generation, drug release, cytotoxicity, and tumor suppression efficacy under X-ray irradiation. BM-DOX@BSA NPs exhibited pH-responsive degradation, releasing DOX more rapidly in acidic conditions. They markedly increased the generation of ROS under X-ray irradiation, resulting in enhanced apoptosis of tumor cells and DNA damage. This effectively improved the efficacy of radiation dynamic therapy (RDT). In vivo, the NPs combined with RT achieved 100% tumor suppression in HepG2 tumor-bearing mice, demonstrating excellent biocompatibility and therapeutic efficacy.