Bimetallic Peroxide Nanocomposites‐Driven Redox Dyshomeostasis to Activate Sequential Cuproptosis and Pyroptosis for Amplified Tumor Immunotherapy

Although metal peroxides are extensively employed in tumor therapy, novel synergistic tumor treatment approaches based on the combination of multiple types of metal peroxides are still lacking and warrant further exploration. To overcome this challenge, hyaluronic acid (HA)-modified bimetallic peroxide nanocomposites (MgO₂-CuO₂@HA NCs) are developed by combining magnesium peroxide (MgO₂) nanosheets and short-grained copper peroxide (CuO₂) nanodots. By modifying HA to enhance tumor targeting and stability, MgO₂-CuO₂@HA NCs leverage pH-dependent decomposition to release Mg²⁺, H₂O₂, and Cu²⁺ under acidic conditions, thereby initiating Fenton-like reactions for the generation of hydroxyl radicals (•OH), while simultaneously depleting glutathione to generate Cu⁺. This process induces cuproptosis through the Cu⁺-mediated oligoaggregation of dihydrolipoamide S-acetyltransferase. Additionally, enhanced •OH activates pyroptosis via the caspase-1/gasdermin D pathway. Cuproptosis and pyroptosis can induce immunogenic cell death, thereby triggering the anti-tumor immune responses. Notably, released Mg²⁺ can enhance the activation of CD8⁺ T cells by promoting the conformational activation of leukocyte function-associated antigen 1. Therefore, this study establishes a novel paradigm for synergistic anti-tumor immunotherapy based on bimetallic peroxide nanocomposites, offering promising prospects for clinical immunotherapy.