pH-Responsive GOx@Cu-ZIF-8/DOX nanoplatform combines chemodynamic therapy, chemotherapy, and glucose deprivation for enhanced antitumor efficacy

The tumor microenvironment (TME), characterized by hypoxia, limited H 2 O 2 availability, and elevated glutathione (GSH) concentrations, challenges reactive oxygen species (ROS)-based therapies. To address these, we developed a GOx@Cu-ZIF-8/DOX (GCZD) nanoplatform combining chemotherapy (CT), chemodynamic therapy (CDT), and starvation therapy (ST). This system utilizes Cu-incorporated ZIF-8 (Cu-ZIF-8) as a versatile carrier to load glucose oxidase (GOx) and doxorubicin (DOX). Under acidic TME conditions, GCZD disintegrates, releasing GOx, Cu 2+ , and DOX. GOx catalyzes intratumoral glucose oxidation, producing gluconic acid and H 2 O 2 to achieve a triple-therapeutic effect. Gluconic acid maintains a weakly acidic environment for continuous GCZD degradation. Glucose depletion induces metabolic starvation. Generated H₂O₂ serves as substrate for Cu 2+ -mediated Fenton-like reactions, boosting ROS production. Cu 2+ exhibits catalytic activity, efficiently converting TME and GOx-generated H 2 O 2 into cytotoxic ·OH. Increased ROS concentration enhances biological macromolecule oxidation damage, intensifying CDT. Additionally, Cu 2+ oxidizes GSH to form GSSH and Cu + . This inhibits GSH-mediated ROS degradation and leverages excellent Fenton-like activity of Cu + to further enhance CDT. Simultaneously, DOX exerts chemotherapeutic effects by intercalating into DNA and inhibiting topoisomerase II, blocking tumor cell proliferation. This integrated approach, combining enhanced ROS generation, tumor cell metabolic intervention, and DNA damage, demonstrates enhanced antitumor efficacy by simultaneously targeting multiple cancer cell vulnerabilities.