Tumor microenvironment-activatable, glucose oxidase-templated nanocatalyst for self-reinforcing starvation and...

Glucose oxidase (GOx)-based starvation therapy (ST) is limited by tumor hypoxia, restricted substrate availability, and inefficient enzyme utilization in carrier-based systems. Here, we developed a tumor microenvironment-responsive GOx-templated MnO₂/Co²⁺ (GMC) nanocatalyst for synergistic ST and chemodynamic therapy (CDT). GMC was prepared in one step, in which GOx served as both a therapeutic component and a template for the in situ formation of MnO₂ and incorporation of Co²⁺, achieving an enzyme loading of approximately 42 wt% while retaining 94.6% of the glucose-oxidation activity of free GOx. In the acidic and H₂O₂-rich tumor microenvironment, GMC decomposed to release catalytic components and generate O₂, thereby alleviating hypoxia. GOx-mediated glucose oxidation subsequently produced H⁺ and H₂O₂, promoting MnO₂ degradation and Co²⁺-mediated Fenton-like reactions for hydroxyl radical generation. Among the tested formulations, GMC showed the most pronounced glucose-dependent reactive oxygen species generation and cytotoxicity in SCC7 cells. In vivo, intratumoral GMC administration produced the greatest antitumor effect among the tested formulations, achieving 74% tumor growth inhibition and an 82% reduction in tumor weight without detectable systemic toxicity. These findings demonstrate that GMC integrates hypoxia relief, ST, and CDT in a self-amplifying catalytic system and represents a potential strategy for localized cancer treatment.