Biomimetic Iridium‐Based Photothermal Nanozyme to Trigger Ferroptosis and Pyroptosis and Activate the cGAS‐STING Pathway for Improved Tumor Immunotherapy

ABSTRACT Although nanozymes are potential tumor therapeutics due to their ability to disrupt intracellular redox homeostasis, developing nanozymes with higher therapeutic efficacy and clarifying their antitumor mechanism are challenging. Here, an iridium (Ir)‐based nanozyme (IIN) was constructed through coordination‐driven co‐assembly using photosensitizer indocyanine green (ICG), Ir, and indoleamine 2,3‐dioxygenase (IDO) inhibitor NLG8189. Then, the IIN was mimicked by tumor cell lysate (TCL)‐simulated dendritic cell (DC) membrane to form IIN@M. Based on superior enzyme‐like activity and photothermal performance, IIN@M disrupted the intracellular redox homeostasis by generating reactive oxygen species (ROS) and depleting glutathione (GSH). GSH depletion induced ferroptosis, and ROS burst under photothermal irradiation triggered pyroptosis, thus synergistically enhancing immunogenic cell death (ICD). The generated ROS could promote mitochondrial DNA (mtDNA) oxidative damage and release, finally activating the immune response by the cyclic GMP‐AMP synthase‐simulator of interferon gene (cGAS‐STING) pathway. In vivo experiments also suggested that IIN@M could efficiently ablate the primary tumor, especially under photothermal irradiation. Furthermore, it could suppress distant tumor progression by triggering the immune response, especially under photothermal irradiation, which was accompanied by increased DC maturation, M1 macrophage polarization, and T cell infiltration in tumor tissue. This study proposed a promising strategy for effective Ir‐based nanozyme in tumor immunotherapy.