Self-cascade nanohybrids boost cell ferroptosis stress for tumor radiosensitization therapy

Although ferroptosis plays a potential role in sensitizing tumor radiotherapy, its radiosensitization efficacy is still limited by insufficient endogenous H2O2 and excess glutathione (GSH) in the tumor microenvironment (TME). Herein, we engineered a “four-in-one” self-cascade nanohybrid composed of MnO2 nanodots-encompassed and bovine serum albumin (BSA)-coated gold nanoclusters (BAM) for radiosensitization therapy of tumors by reprogramming tumor cell fate to ferroptosis and reshaping TME. The MnO2 nanodots possessed fascinating glucose oxidase (GOx)-mimicking activity to effectively catalyze tumor endogenous glucose into H2O2, could further decompose H2O2 into hydroxyl radicals (HO·) and O2 in response to acidic TME, and simultaneously depleted the endogenous GSH, breaking the redox homeostasis in TME. As a result, lipid peroxides (LPO) in cell membranes and ferroptosis stress of tumor cells were significantly up-regulated. Synergy with the hypoxia relief and enhancement by the gold nanocores, radiotherapy completely inhibited the tumor progression. Moreover, the gold nanocores were successfully radiolabeled with 64Cu, and PET imaging revealed that BAM had high tumor-targeting efficiency and was renally clearable. Our study provides a unique perspective on radiosensitization therapy by regulating tumor cell fate to ferroptosis through rational design of a self-cascade nanozyme.