Oxidative stress is a compelling risk factor in chronic kidney diseases and is further aggravated for individuals during extracorporeal blood purification, ultimately leading to multiple complications. Herein, antioxidative cascade metal-phenolic nanozymes (metal-tannic acid nanozymes, M-TA NMs) are synthesized via metal ions-mediated oxidative coupling of polyphenols; then M-TA NMs engineered hemoperfusion microspheres (Cu-TAn@PMS) are constructed for alleviating oxidative stress. M-TA NMs show adjustable broad-spectrum antioxidative activities toward multiple reactive nitrogen and oxygen species (RNOS) due to the adjustable catalytic active centers. Importantly, M-TA NMs could mimic the cascade processes of superoxide dismutase and catalase to maintain intracellular redox balance. Detailed structural and spectral analyses reveal that the existence of a transition metal could decrease the electronic energy band gaps of M-TA NMs to offer better electron transfers for RNOS scavenging. Notably, dynamic blood experiments demonstrate that Cu-TAn@PMS could serve as an antioxidant defense system for blood in hemoperfusion to scavenge intracellular reactive oxygen species (ROS) effectively even in the complex blood environment and further protect endogenous antioxidative enzymes and molecules. In general, this work developed antioxidative cascade nanozymes engineered microspheres with excellent therapeutic efficacy for the treatment of oxidative stress-related diseases, which exhibited potential for clinical blood purification and extended the biomedical applications of nanozymes.

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