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 (<i>e.g.</i>, 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. <i>In vitro</i> and <i>in vivo</i> 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). <i>In vivo</i>, the NPs combined with RT achieved 100% tumor suppression in HepG2 tumor-bearing mice, demonstrating excellent biocompatibility and therapeutic efficacy.