Charge‐Tunable Dense Dual‐Atom Nanozymes Reprogram Biothiol Metabolism Through Multi‐Enzyme‐Mimetic Catalysis to Synergistically Induce Ferroptosis and Disulfidptosis

Abstract

ABSTRACT Biothiols play a pivotal role in maintaining cellular redox homeostasis, coordinating programmed cell death pathways, and modulating immune responses. Reprogramming biothiol metabolism in tumor cells thus presents a promising strategy for enhancing anti‐tumor immunity. Here, we report the rational design of a densely accessible heteronuclear Fe/Co dual‐atom nanozyme (FeCo DDA), which mimics natural flavoenzymes by coordinating high‐density Fe and Co active centers to regulate biothiol metabolism and induce intracellular disulfide accumulation. The dense heteronuclear diatomic catalytic center (with Fe and Co mass fractions of 10.35% and 11.32%, respectively) optimizes the Bader charge and d‐band center by adjusting electron redistribution, endowing it with excellent mimetic enzymatic activities for catalyzing the oxidation of biothiols to disrupt the homeostasis of tumor cells. Simultaneously, co‐loaded phlorizin inhibits glucose uptake, further driving compensatory cystine accumulation and disrupting glutathione biosynthesis. This dual action synergistically induces ferroptosis‐enhanced disulfidptosis, disrupting redox homeostasis and triggering immunogenic cell death. As a result, FeCo DDA co‐loaded with phlorizin (FeCo DDA/P) not only enhances tumor cell immunogenicity but also reshapes the immunosuppressive tumor microenvironment, thereby potentiating anti‐tumor immune responses. This work highlights a dual‐atom nanozyme strategy to reprogram tumor metabolism and orchestrate multimodal cell death for effective tumor immunotherapy.