Dual-Enzyme-Driven Thermosensitive Hydrogel Triggers Disulfidptosis and Alleviates Hypoxia for Enhanced Osteosarcoma Radiosensitization.

Osteosarcoma shows poor responsiveness to radiotherapy (RT), largely due to the efficient DNA damage repair capacity of tumor cells and the hypoxic tumor microenvironment. In addition, achieving adequate safe surgical margins after resection remains difficult, contributing to low long-term patient survival. Current clinical radiosensitization strategies are limited by insufficient tumor specificity and considerable systemic toxicity. In this study, we loaded glucose oxidase (GOx) and catalase (CAT) into a thermosensitive hydrogel to construct a local cascade catalytic system, termed FS-GC. The SLC7A11-mediated conversion of cystine to cysteine is highly dependent on glucose availability. GOx consumes glucose and depletes NADPH, increasing the NADP+/NADPH ratio and promoting cystine accumulation. This triggers filamentous actin contraction and downregulation of filamin A, thereby inhibiting DNA repair proteins and inducing disulfidptosis. Meanwhile, CAT converts H2O2 generated by GOx into oxygen to alleviate local hypoxia. FS-GC exhibits favorable biosafety, structural stability, and sustained enzyme release and degrades almost completely within 14 days. In vitro and in vivo results confirm that FS-GC suppresses DNA repair and relieves hypoxia through disulfidptosis and the dual catalytic activity of GOx and CAT, leading to significantly enhanced RT efficacy and inhibition of osteosarcoma progression.