A Degradable Nanoplatform Integrating Glucose Oxidase and Copper Selenide for Near-Infrared-Enhanced Multimodal Synergistic Therapy in Lung Cancer.

Lung cancer remains a leading cause of cancer-related mortality worldwide, with therapeutic outcomes frequently constrained by drug resistance, tumor heterogeneity, and systemic toxicity. Multimodal synergistic therapy has emerged as a promising strategy to address these challenges. In this study, we developed a biodegradable nanosystem, designated CSZG, which integrates glucose oxidase (GOx) and copper-rich copper selenide (Cu2-x Se) within a ZIF-8 nanocarrier for lung cancer therapy. CSZG exhibited pH-responsive GOx release, favorable colloidal stability, and retained glucose-responsive catalytic activity of GOx. GOx supplied hydrogen peroxide (H2O2) through glucose oxidation, while Cu+ catalyzed the conversion of H2O2 into cytotoxic hydroxyl radicals (•OH) under near-infrared (NIR) irradiation, thereby enhancing chemodynamic therapy. Electron spin resonance analysis directly confirmed NIR-enhanced •OH generation, particularly under acidic conditions. In addition, CSZG + NIR induced copper-dependent mitochondrial dysfunction with cuproptosis-associated features, as evidenced by aggregation of dihydrolipoamide S-acetyltransferase, down-regulation of ferredoxin 1 , depletion of Fe-S cluster proteins, and partial reversal by tetrathiomolybdate. The Cu2-x Se-containing platform also promoted macrophage polarization toward an M1-like phenotype. In vivo, CSZG + NIR achieved a tumor inhibition rate of 91.7% and demonstrated favorable short-term systemic biosafety under the tested therapeutic conditions. Collectively, these findings highlight CSZG as a promising multimodal therapeutic platform for lung cancer.