NIR‐Activatable Domino Cascade Catalysis Nanozyme Reactor for Multi‐Mechanism Synergistic Immunotherapy in Bladder Cancer

Abstract Current intravesical therapies for bladder cancer after resection are limited by poor tissue penetration, off‐target effects, and insufficient efficacy. To address these challenges, this study designs a thermo‐responsive hydrogel (PNH) that encapsulates chitosan (CS)‐coated Fe/Mn bimetallic nanozymes (FMCC) together with cholesterol oxidase (ChOx). FMCC displays multiple enzyme‐mimicking activities, including peroxidase (POD), catalase (CAT), and glutathione oxidase (GSHox). ChOx amplifies this catalytic cascade, enhancing reactive oxygen species (ROS) production and inducing ferroptosis‐mediated tumor cell death. The CS coating improves mucosal adhesion and tissue permeability, thereby facilitating intravesical delivery. Upon near‐infrared (NIR) irradiation, FMCC generates heat that liquefies the hydrogel, enabling spatiotemporally controlled drug release and providing mild photothermal therapy (MPTT). This photothermal effect acts synergistically with ferroptosis induction and immune modulation, concurrently minimizing damage to normal tissues. In parallel, ChOx disrupts cholesterol‐rich membrane rafts and promotes pro‐inflammatory M1 macrophage polarization. Released Mn 2+ ions further potentiate immune activation by stimulating the cGAS–STING pathway, driving IFN‐β and IL‐6 secretion, dendritic cell maturation, and T cell infiltration. Together, this nanozyme–hydrogel system integrates tissue penetration, metabolic disruption, and immune stimulation, representing a promising strategy for localized bladder cancer therapy.