One‐Step Symbiosis of Bimetallic Peroxides Nanoparticles to Induce Ferroptosis/Cuproptosis and Activate cGAS‐STING Pathway for Enhanced Tumor Immunotherapy

Abstract To improve the efficiency and application prospects of metal peroxides in tumor therapy, the synthesis of bimetallic peroxides via simple yet effective approaches will be highly significant. In this work, hyaluronic acid modified zinc‐copper bimetallic peroxides (ZCPO@HA) nanoparticles are synthesized through a one‐step symbiotic method by co‐hydrolysis of zinc acetate and copper acetate in weakly alkaline solution, followed by modification with sodium hyaluronate. Upon decomposition in the tumor microenvironment, ZCPO@HA nanoparticles can generate a considerable content of hydroxyl radical (·OH) by Fenton‐like reaction between Cu ²⁺ and self‐compensating hydrogen peroxide, while downregulating the expression of glutathione peroxidase 4 to induce ferroptosis. The abundant release of Cu ²⁺ leads to the aggregation of dihydrolipoamide S‐acetyltransferase and the reduction of iron‐sulfur cluster proteins, causing cuproptosis. The immunogenic cell death of tumor cells releases abundant damage associated molecular patterns, effectively activating the adaptive immune response. Zn ²⁺ and ·OH cause mitochondrial damage, leading to the release of a substantial amount of mitochondrial DNA. This subsequently activates the cyclic guanosine monophosphate‐adenosine monophosphate synthase‐stimulator of interferon genes (cGAS‐STING) pathway, enhancing the innate immune response. In conclusion, it synthesizes a new type of bimetallic peroxides by one‐step symbiosis for activating anti‐tumor immunotherapy combined with immune checkpoint inhibitor.