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However, the complex microenvironment and limited joint space result in rapid clearance of drugs. Herein, a nanogel\u2010based strategy is proposed for prolonged drug delivery and microenvironment remodeling. Nanogel is constructed through the functionalization of hyaluronic acid (HA) by amide reaction on the surface of Kartogenin (KGN)\u2010loaded zeolitic imidazolate framework\u20108 (denoted as KZIF@HA). Leveraging the inherent hydrophilicity of HA, KZIF@HA spontaneously forms nanogels, ensuring extended drug release in the OA microenvironment. KZIF@HA exhibits sustained drug release over one month, with low leakage risk from the joint cavity compared to KZIF, enhanced cartilage penetration, and reparative effects on chondrocytes. Notably, KGN released from KZIF@HA serves to promote extracellular matrix (ECM) secretion for hyaline cartilage regeneration. Zn\n                    <jats:sup>2+<\/jats:sup>\n                    release reverses OA progression by promoting M2 macrophage polarization to establish an anti\u2010inflammatory microenvironment. Ultimately, KZIF@HA facilitates cartilage regeneration and OA alleviation within three months. Transcriptome sequencing validates that KZIF@HA stimulates the polarization of M2 macrophages and secretes IL\u201010 to inhibit the JNK and ERK pathways, promoting chondrocytes recovery and enhancing ECM remodeling. This pioneering nanogel system offers new therapeutic opportunities for sustained drug release, presenting a significant stride in OA treatment strategies.\n                  <\/jats:p>","DOI":"10.1002\/adma.202401094","type":"journal-article","created":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T18:52:22Z","timestamp":1714416742000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":88,"title":["Self\u2010Reinforced MOF\u2010Based Nanogel Alleviates Osteoarthritis by Long\u2010Acting Drug Release"],"prefix":"10.1002","volume":"36","author":[{"given":"Yun","family":"Sun","sequence":"first","affiliation":[{"name":"Beijing Advanced Innovation Center for Soft Matter Science and Engineering State Key Laboratory of Organic\u2013Inorganic Composites Bionanomaterials &amp; Translational Engineering Laboratory Beijing Key Laboratory of Bioprocess Beijing Laboratory of Biomedical Materials Beijing University of Chemical Technology 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