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

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.