“Spark” PtMnIr Nanozymes for Electrodynamic‐Boosted Multienzymatic Tumor Immunotherapy

Multienzyme‐mimicking redox nanozymes capable of efficient reactive oxygen species (ROS) generation and cellular homeostasis disruption are highly pursued for cancer therapy. However, it still faces challenges from the complicate tumor microenvironment (TME) and high chance for tumor metastasis. Herein, well‐dispersed PtMnIr nanozymes are designed with multiple enzymatic activities, including catalase (CAT), oxidase (OXD), superoxide dismutase (SOD), peroxidase (POD), and glutathione peroxidase (GPx), which continuously produce ROS and deplete glutathione (GSH) concurrently in an “inner catalytic loop” way. With the help of electrodynamic stimulus, highly active “spark” species (Ir3+ and Mn3+) are significantly increased, resulting in an effective cascade enzymatic and electrodynamic therapy. Moreover, the cyclic generation of ROS can also facilitate ferroptosis and apoptosis in tumor cells, boosting synergistic therapy. Importantly, lung metastasis inhibition is found, which confirms efficient immunotherapy by the combined effect of immunogenic cell death (ICD) and Mn2+‐induced cyclic guanosine monophosphate (GMP)–adenosine monophosphate (AMP) synthase (cGAS)–stimulator of interferon genes (cGAS–STING) pathway, contributing great potential in the treatment of malignant tumors. PtMnIr nanozymes exhibit pentaenzymatic activities for reactive oxygen species generation and glutathione consumption. Under alternating current stimulation, highly active “spark” species (Ir3+ and Mn3+) are significantly increased for enzymatic/electrodynamic synergistic oncotherapy. PtMnIr nanozymes can also activate immune pathways (immunogenic cell death and Mn2+‐induced cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes) and inhibit the tumor metastasis.