A Hydrogen‐Releasing Nanozyme Engineers a Mitochondrial ROS Amplifier for Self‐Sustaining Catalytic Immunotherapy

ABSTRACT The efficacy of nanocatalytic therapy is constrained by the limited availability of endogenous hydrogen peroxide (H 2 O 2 ) as a reaction substrate, finite catalytic activity of nanozymes and rapid scavenging by intracellular antioxidants, hindering their accumulation at target sites to therapeutic concentrations. To address the core bottleneck, we developed a hydrogen‐doped rhodium‐palladium alloy (RhPd‑H) nanozyme that integrates enhanced peroxidase (POD)‐mimetic catalytic activity with thermally triggered hydrogen gas (H 2 ) release. Under near‐infrared (NIR) irradiation, the RhPd‐H performs POD activity to efficiently produce exogenous hydroxyl radicals (·OH), inducing initial oxidative stress. Concurrently, the released H 2 flux could reduce the level of reactive oxygen species (ROS) within mitochondria, thereby mitigating oxidative damage and reprogramming mitochondria into endogenous ROS generator that continuously leak superoxide anion (·O 2 − ). This dual‐path ROS generation mechanism sustains prolonged intracellular ROS burst to efficiently kill tumor cells. Further, in vivo evaluations demonstrated that RhPd‐H nanoenzyme exhibited long‐term tumor retention, significant suppression of tumor growth and activation of antitumor immunity. By differentially regulating ROS across space and time, RhPd‑H nanozyme establishes a persistent and overwhelming oxidative stress that effectively disrupts redox homeostasis. Our work advances beyond conventional catalytic therapy, proposing a new concept of metabolically amplified nanozyme therapy.