Nanozymes are widely applied for treating various major diseases, including neurological diseases and tumors. However, the biodegradability of nanozymes remains a great challenge, which hinders their further clinical translation. Based on the microenvironment of osteoarthritis (OA), a representative pH‐responsive biodegradable hollow‐structured manganese Prussian blue nanozyme (HMPBzyme) is designed and applied for treatment of OA. HMPBzyme with good pH‐responsive biodegradability, biocompatibility, and multi‐enzyme activities is constructed by bovine serum albumin bubbles as a template‐mediated biomineralization strategy. HMPBzyme suppresses hypoxia‐inducible factor‐1α (HIF‐1α) expression and decreases reactive oxygen species (ROS) level in the in vitro experiment. Furthermore, HMPBzyme markedly suppresses the expression of ROS and alleviates the degeneration of cartilage in OA rat models. The results indicate that the biodegradable HMPBzyme inhibits oxidative damage and relieves hypoxia synergistically to suppress inflammation and promote the anabolism of cartilage extracellular matrix by protecting mitochondrial function and down‐regulating the expression of HIF‐1α, which modulates the phenotypic conversion of macrophages from pro‐inflammatory M1 subtype to anti‐inflammatory M2 subtype for OA treatment. This research lays a solid foundation for the design, construction, and biomedical application of biodegradable nanozymes and promotes the application of nanozymes in biomedicine.

Oxidative stress and excessive inflammatory responses are the two critical mechanisms of hepatic ischemia-reperfusion injury (HIRI) encountered in many clinical settings, including following hepatectomy and liver transplantation. Effective anti-inflammatory and anti-oxidative pharmacological interventions are urgently needed to counter HIRI. The present study showed that a biocompatible Prussian blue (PB) scavenger with reactive oxygen species (ROS) scavenging and anti-inflammatory properties might be used a promising treatment for HIRI. Following intravenous administration, PB scavenger was mainly distributed in the liver, where it showed excellent ability to alleviate apoptosis, tissue injury and organ dysfunction after HIRI. PB scavenger was found to protect liver tissue by scavenging ROS, reducing neutrophil infiltration and promoting macrophage M2 polarization. In addition, PB scavenger significantly reduced oxidative stress in primary hepatocytes, restoring cell viability under oxidative stress condition. PB scavenger effectively reduced lipopolysaccharide-stimulated inflammation in RAW 264.7 cells. These findings indicate that PB scavenger may be a potential therapeutic agent for the treatment of HIRI, providing an alternative treatment for ROS-associated and inflammatory liver diseases.

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