Tumor microenvironment-responsive metal-natural polyphenol nanozyme for radiosensitization by interfering glucose metabolism and redox homeostasis

Radiotherapy (RT) still faces great challenges with tumor hypoxia, antioxidant mechanisms and high glucose metabolism. Herein, we report a tumor microenvironment (TME)-responsive ruthenium-natural polyphenol phloretin (RPP) nanozyme with glucose oxidase (GOx), catalase (CAT), peroxidase (POD) and glutathione peroxidase (GPX) -like activities, which serves as an efficient and safe radiosensitizer for enhanced RT. Under an acidic TME, RPP nanozyme aerobically consumes the intracellular glucose and reduces the production of lactic acid, and meanwhile, the in-situ exposure of phloretin can block the uptake of extracellular glucose by inhibiting glucose transporters, making it more efficient to inhibit glycolysis and minimize oxygen consumption. Moreover, RPP nanozyme can not only rapidly catalyze hydrogen peroxide (H₂O₂) into reactive oxygen species (ROS) and oxygen to alleviate tumor hypoxia, but also down-regulate the intracellular glutathione (GSH) and lactic acid level to overcome antioxidant metabolism. Both in vitro and in vivo studies manifest that RPP nanozyme significantly enhance the radiosensitivity of 4 T1 tumor cells. Besides, in vivo positron emission tomography imaging, utilizing clinical imaging agents, validates the decreased glucose uptake and hypoxia relief treated by RPP nanozyme. The facile RPP nanozyme with the regulating ability of TME can achieve TME-responsive radiosensitization, providing promising potential for tumor therapy.