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

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.