Clinical applications of nanozyme-initiated chemodynamic therapy (NCDT) have been severely limited by the poor catalytic efficiency of nanozymes, insufficient endogenous hydrogen peroxide (H₂ O₂ ) content, and its off-target consumption. Herein, the authors developed a hollow mesoporous Mn/Zr-co-doped CeO₂ tandem nanozyme (PHMZCO-AT) with regulated multi-enzymatic activities, that is, the enhancement of superoxide dismutase (SOD)-like and peroxidase (POD)-like activities and inhibition of catalase (CAT)-like activity. PHMZCO-AT as a H₂ O₂ homeostasis disruptor promotes H₂ O₂ evolution and restrains off-target elimination of H₂ O₂ to achieve intensive NCDT. PHMZCO-AT with SOD-like activity catalyzes endogenous superoxide anion (O₂ ^•- ) into H₂ O₂ in the tumor region. The suppression of CAT activity and depletion of glutathione by PHMZCO-AT largely weaken the off-target decomposition of H₂ O₂ to H₂ O. Elevated H₂ O₂ is then catalyzed by the downstream POD-like activity of PHMZCO-AT to generate toxic hydroxyl radicals, further inducing tumor apoptosis and death. T₁ -weighted magnetic resonance imaging and X-ray computed tomography imaging are also achieved using PHMZCO-AT due to the existence of paramagnetic Mn²⁺ and the high X-ray attenuation ability of elemental Zr, permitting in vivo tracking of the therapeutic process. This work presents a typical paradigm to achieve intensive NCDT efficacy by regulating multi-enzymatic activities of nanozymes to perturb the H₂ O₂ homeostasis.

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