Copper peroxide-triggered reactive nitrogen effectively enhanced synergistic chemodynamic-immunotherapy

Overcoming the limitations of chemodynamic therapy (CDT), constrained by the transient nature and limited bioavailability of reactive oxygen species (ROS), this study proposes a synergistic strategy integrating CDT with immunotherapy. We engineered a multifunctional nanocarrier, HMSN-Met@HA-CuO₂, leveraging CuO₂ to amplify intracellular ROS generation and induce cuproptosis. Concurrently, metformin (Met) releases nitric oxide (NO), which scavenges ROS to generate more stable reactive nitrogen species (RNS). These RNS elicit sustained and irreversible damage to lipids, proteins, and deoxyribonucleic acid (DNA), resulting in potent tumor cell cytotoxicity and activation of an antitumor immune response. This work demonstrates the potential of an autonomously driven conversion from oxygen radicals to nitrogen radicals, coupled with the enhanced combinatorial application of CDT and immunotherapy, significantly improving antitumor efficacy.