Bioinspired Dual‐Ionic‐Site Single‐Atom Nanozymes for Synergistic Ferroptosis/Cuproptosis and Enhanced Immune Checkpoint Blockade Therapy

Abstract Clinical cancer patients often exhibit limited responses to immunotherapy, primarily due to the low immunogenicity of solid tumors and insufficient T cell infiltration, which reduce the effectiveness of immune checkpoint blockade (ICB) therapy. To address this challenge, a Fe 3+ /Cu 2+ dual‐ionic‐site single‐atom nanozyme (dis‐SAzyme) is constructed with multiple catalytic active sites, which can catalyze ROS generation and deplete antioxidants, thereby inducing synergistic ferroptosis and cuproptosis to enhance immunogenicity. Camouflaging doxorubicin‐loaded dis‐SAzyme with a bioinspired cancer cell membrane (dis‐SAzyme‐Dox@M) enables targeted navigation to the tumor region, leading to selective ferroptosis/cuproptosis in cancer cells. This synergistic ferroptosis and cuproptosis polarize tumor‐associated macrophages to an antitumoral M1 phenotype while reducing protumoral M2 population by inducing M2 macrophage ferroptosis. This process may synergize with mature dendritic cells by promoting the releasing of various cytosolic contents and inflammatory factors, thereby enhancing antigen presentation and triggering the immunogenic cell death. Additionally, dis‐SAzyme‐Dox@M induces a substantial increase in antitumor infiltrating CD8 + T cells and a remarkable decrease in CD4 + regulatory T cells. The combination of dis‐SAzyme‐Dox@M with αPD‐1 effectively eradicates hepatocellular carcinoma in vivo. This strategy offers a novel approach to designing dis‐SAzymes and provides valuable perspectives into advancing the combination of catalytic therapy, chemotherapy, and enhanced immunotherapy.