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Yet currently no attention has been paid to fabricating hypoxia\u2010responsive platforms for OA treatment. Herein, an injectable hydrogel microsphere system (HAM\u2010SA@HCQ) focusing on the hypoxic inflamed joint is prepared with methacrylate\u2010modified sulfonated azocalix[4]arene (SAC4A\u2010MA), methacrylated hyaluronic acid (HA\u2010MA), and dithiol\u2010terminated matrix metalloproteinase 13 (MMP\u201013) sensitive peptide via a microfluidic device and photo crosslinking technique, followed by encapsulation of the anti\u2010inflammatory drug hydroxychloroquine (HCQ) through host\u2013guest interaction. Owing to the hydrophobic deep cavity, phenolic units, and azo bonds of SAC4A\u2010MA, the hydrogel microspheres show strong drug loading capacity, prominent reactive oxygen species (ROS) scavenging capability, and specific hypoxia\u2010responsive drug release ability. In the OA tissue microenvironment, the hydrogel microspheres undergo degradation by excessive MMP\u201013 and release HCQ under the hypoxia condition, which synergizes with the ROS\u2010scavenging calixarene to inhibit the inflammatory response of macrophages. After being injected into the OA\u2010inflamed joint, the HAM\u2010SA@HCQ can significantly attenuate the oxidative stress, downregulate the expression of hypoxia\u2010induced factor\u20101\u03b1 and inflammatory cytokines, and prevent the cartilage from being destroyed.<\/jats:p>","DOI":"10.1002\/smll.202308599","type":"journal-article","created":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T13:23:53Z","timestamp":1701869033000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Hypoxia and Matrix Metalloproteinase 13\u2010Responsive Hydrogel Microspheres Alleviate Osteoarthritis Progression In Vivo"],"prefix":"10.1002","volume":"20","author":[{"given":"Tong","family":"Zhou","sequence":"first","affiliation":[{"name":"MOE Key Laboratory of Macromolecular Synthesis and Functionalization Department of Polymer Science and Engineering Zhejiang University  Hangzhou 310058 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