The insufficient intracellular H2O2 level in tumor cells is closely associated with the limited efficacy of chemodynamic therapy (CDT). Despite tremendous efforts, engineering CDT agents with a straightforward and secure H2O2 supplying ability remains a great challenge. Inspired by the balance of H2O2 generation and elimination in cancer cells, herein, a nanozyme-based H2O2 homeostasis disruptor is fabricated to elevate the intracellular H2O2 level through facilitating H2O2 production and restraining H2O2 elimination for enhanced CDT. In the formulation, the disruptor with superoxide dismutase-mimicking activity can convert O2 •– to H2O2, promoting the production of H2O2. Simultaneously, the suppression of catalase activity and depletion of glutathione by the disruptor weaken the transformation of H2O2 to H2O. Thus, the well-defined system could perturb the H2O2 balance and give rise to the accumulation of H2O2 in cancer cells. The raised H2O2 level would ultimately amplify the Fenton-like reaction-based CDT efficiency. Our work not only paves a way to engineer alternative CDT agents with a H2O2 supplying ability for intensive CDT but also provides new insights into the construction of bioinspired materials.

Sepsis, characterized by immoderate production of multiple reactive oxygen and nitrogen species (RONS), causes high morbidity and mortality. Despite progress made with nanozymes, efficient antioxidant therapy to eliminate these RONS remains challenging, owing largely to the specificity and low activity of exploited nanozymes. Herein, an enzyme‐mimicking single‐atom catalyst, Co/PMCS, features atomically dispersed coordinatively unsaturated active Co‐porphyrin centers, which can rapidly obliterate multiple RONS to alleviate sepsis. Co/PMCS can eliminate O2.− and H2O2 by mimicking superoxide dismutase, catalase, and glutathione peroxidase, while removing .OH via the oxidative‐reduction cycle, with markedly higher activity than nanozymes. It can also scavenge .NO through formation of a nitrosyl–metal complex. Eventually, it can reduce proinflammatory cytokine levels, protect organs from damage, and confer a distinct survival advantage to the infected sepsis mice.