Nanozyme as tumor energy homeostasis disruptor mediated ferroptosis for high-efficiency radiotherapy.

Radioresistance in tumors, driven by the insufficiency and rapid depletion of reactive oxygen species (ROS), limits the efficacy of radiotherapy (RT). This study introduces an Ir@Au nanozyme that enhances tumor radiosensitivity by disrupting energy homeostasis and inducing ferroptosis in tumor cells. The Ir@Au nanozyme mimics glucose oxidase to block the tumor's energy supply, continuously produces hydrogen peroxide (H2O2), and lowers the pH to optimize Fenton reactions. Acting as a peroxidase (POD), it generates additional ROS for chemodynamic therapy (CDT), depletes glutathione (GSH), and perturbs the tumor's antioxidant defenses. Upon exposure to ionizing radiation, the nanozyme absorbs photons and emits electrons, interacting with water to amplify ROS production. This ROS accumulation, combined with radiation, enhances DNA damage and lipid peroxidation, reversing radioresistance and promoting ferroptosis. Additionally, Ir@Au serves as a contrast agent for computed tomography, enabling precise RT through the delineation of tumor boundaries. In summary, the Ir@Au nanozyme effectively disrupts tumor energy homeostasis, initiating ROS-based cascades that inhibit tumor growth. It thus offers a promising strategy for overcoming radioresistance during cancer therapy.