Pairing GOx With a Potent H₂O₂-consuming Co-Cu_xO Nanozyme for Starvation/Cuproptosis/Chemodynamic Synergistic Therapy

Combining glucose oxidase (GOx) with peroxidase-like (POD) nanozymes is a well-established strategy for synergistic starvation and chemodynamic therapy (CDT). However, the low catalytic efficacy of most nanozymes compared to GOx often leads to wasteful accumulation of hydrogen peroxide (H₂O₂), which can inhibit GOx activity and limit the therapeutic effect. Therefore, enhancing the H₂O₂ consumption efficiency is critical to unlocking the full potential of this approach. Here, we designed a cobalt-doped mixed-valence copper oxide (Co-Cu_xO) nanozyme with metals uniformly dispersed using a polyacrylic acid (PAA) scaffolding method. This nanozyme tightly couples the redox cycles that drive the valence state interconversions of cobalt (Co) and copper (Cu) elements, enabling highly efficient consumption of H₂O₂ and glutathione (GSH). While Co provides multi-valent characteristics ideal for Fenton-like reactions, Cu acts not only as a co-catalyst but also triggers cuproptosis. We further installed GOx onto the nanozyme surface, allowing H₂O₂ produced by GOx channels to Co-Cu_xO active sites, thereby further accelerating the catalytic cascade. In vitro experiments demonstrated effective glucose and H₂O₂ depletion with abundant hydroxyl radical (·OH) generation. When functionalized with hyaluronic acid (HA) for tumor targeting, in vivo experiments demonstrated robust multimodal cell death, confirming the high efficacy of our integrated dual-enzyme platform.