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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\u2010responsive biodegradable hollow\u2010structured manganese Prussian blue nanozyme (HMPBzyme) is designed and applied for treatment of OA. HMPBzyme with good pH\u2010responsive biodegradability, biocompatibility, and multi\u2010enzyme activities is constructed by bovine serum albumin bubbles as a template\u2010mediated biomineralization strategy. HMPBzyme suppresses hypoxia\u2010inducible factor\u20101\u03b1\u00a0(HIF\u20101\u03b1)\u00a0expression 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\u2010regulating the expression of HIF\u20101\u03b1, which modulates the phenotypic conversion of macrophages from pro\u2010inflammatory M1 subtype to anti\u2010inflammatory 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.<\/jats:p>","DOI":"10.1002\/smll.202203240","type":"journal-article","created":{"date-parts":[[2022,7,18]],"date-time":"2022-07-18T02:15:42Z","timestamp":1658110542000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":89,"title":["Biodegradable Hollow\u2010Structured Nanozymes Modulate Phenotypic Polarization of Macrophages and Relieve Hypoxia for Treatment of Osteoarthritis"],"prefix":"10.1002","volume":"18","author":[{"given":"Hao","family":"Xiong","sequence":"first","affiliation":[{"name":"Shanghai Jiao Tong University Affiliated Sixth People's Hospital  600 Yishan Road Shanghai 200233 China"},{"name":"Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration  Building 3, Langu Science and Technology Park, Lane 70, Haiji 6th Road Shanghai 201306 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongzheng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University Affiliated Sixth People's Hospital  600 Yishan Road Shanghai 200233 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinyuan","family":"Xu","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University Affiliated Sixth People's Hospital  600 Yishan Road Shanghai 200233 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Xie","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University Affiliated Sixth People's Hospital  600 Yishan Road Shanghai 200233 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianrong","family":"Wu","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University Affiliated Sixth People's Hospital  600 Yishan Road Shanghai 200233 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Hu","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University Affiliated Sixth People's Hospital  600 Yishan Road Shanghai 200233 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Chen","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University Affiliated Sixth People's Hospital  600 Yishan Road Shanghai 200233 China"},{"name":"Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration  Building 3, Langu Science and Technology Park, Lane 70, Haiji 6th Road Shanghai 201306 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojun","family":"Cai","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University Affiliated Sixth People's Hospital  600 Yishan Road Shanghai 200233 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyi","family":"Zheng","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University Affiliated Sixth People's Hospital  600 Yishan Road Shanghai 200233 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7854-5233","authenticated-orcid":false,"given":"Cunyi","family":"Fan","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University Affiliated Sixth People's Hospital  600 Yishan Road Shanghai 200233 China"},{"name":"Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration  Building 3, Langu Science and Technology Park, Lane 70, Haiji 6th Road Shanghai 201306 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,7,17]]},"reference":[{"key":"e_1_2_8_1_1","first-page":"646","volume":"81","author":"Woolf A. 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