H 2 S‐Responsive NIR‐II Fluorescent Nanozyme that Regulates Tumor Microenvironment for Activatable Synergistic CO Therapy/Catalytic Therapy/Immunotherapy

Abstract Nanozyme catalytic therapy triggered by the tumor microenvironment (TME)‐responsive enzyme‐like catalytic activities is an emerging approach for tumor treatment. However, the poor catalytic efficiency of nanozymes in tumors and the toxic side effects on normal tissues limit their further development, primarily due to the limited uptake and penetration depth of nanozyme in tumor tissues. Here, a tumor‐targeting TME and electric field stimuli‐responsive nanozyme (AgPt@CaCO 3 ‐FA) is developed, which is capable of catalyzing the generation of ROS to induce cell death and releasing carbon monoxide (CO) specifically in tumor tissues for on‐demand CO therapy and immunotherapy. Benefiting from the endogenous H 2 S activated NIR‐II fluorescence (FL) imaging guidance, AgPt@CaCO 3 ‐FA can be delivered into the deeper site of tumor tissues resulted from the TME regulation via generated CO during the electrolysis process to improve the catalytic efficiency of nanozymes in tumors. Moreover, CO effectively relieve immunosuppression TME via reeducating tumor‐supportive M2‐like macrophages to tumoricidal M1‐like macrophages and induce mitochondrial dysfunction by reducing mitochondrial membrane potential, triggering tumor cells apoptosis. The enzyme‐like activities combined with CO therapy arouse distinct immunogenic cell death (ICD) effect. Therefore, AgPt@CaCO 3 ‐FA permits synergistic CO gas, catalytic therapy and immunotherapy, effectively eradicating orthotopic breast tumors and preventing tumor metastasis and recurrence.