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However, the clearance of these bio\u2010lubricants mediated by synovial macrophages leads to reduced therapeutic efficiency and adverse inflammatory responses. Herein, it is shown that this process is predominantly mediated by the specific binding of complement C3 (on nanoparticle) and CD11b (on macrophage). More importantly, through a systematic evaluation of various interface modifications, a macrophage\u2010evading nanoparticle strategy is proposed, which not only minimizes friction, but also largely suppresses C3 adsorption. It involves employing a zwitterionic poly\u20102\u2010methacryloyloxyethyl phosphorylcholine (PMPC) brush layer grafted from a crosslinked gelatin core. In vitro studies demonstrate that such a nanoparticle lubricant can evade macrophage phagocytosis and further prevent the pro\u2010inflammatory M1 polarization and subsequent harmful release of cytokines. In vivo studies show that the designed PMPC brush layer effectively mitigates synovial inflammation, alleviates OA\u2010associated pain, and protects cartilage from degeneration, thus preventing OA progression. These findings clarify the pivotal role of complement C3\u2010mediated macrophage recognition in nanoparticles clearance and offer a promising nanoparticle design strategy to restore joint lubrication.<\/jats:p>","DOI":"10.1002\/adma.202501137","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T05:55:11Z","timestamp":1745992511000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Zwitterionic Brush\u2010Grafted Interfacial Bio\u2010Lubricant Evades Complement C3\u2010Mediated Macrophage Phagocytosis for Osteoarthritis Therapy"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7724-9679","authenticated-orcid":false,"given":"Chuandong","family":"Cai","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Institute of Bone and Joint Diseases Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingwei","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering State\u2010Key Laboratory of Chemical Engineering and Shanghai Key Laboratory of Multiphase Materials Chemical Engineering East China University of Science and Technology  Shanghai 200237 China"},{"name":"Department of Dentistry\u2010Regenerative Biomaterials Radboud University Medical Center  Nijmegen 6525 EX The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luman","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Institute of Bone and Joint Diseases Fudan University  Shanghai 200032 China"},{"name":"Department of Immunology, School of Basic Medical Sciences Shanghai Key Laboratory of Medical Epigenetics and Metabolism Institutes of Biomedical Sciences Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangtao","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering State\u2010Key Laboratory of Chemical Engineering and Shanghai Key Laboratory of Multiphase Materials Chemical Engineering East China University of Science and Technology  Shanghai 200237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lipeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Institute of Bone and Joint Diseases Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingkai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Institute of Bone and Joint Diseases Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guohao","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Institute of Bone and Joint Diseases Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingxuan","family":"Hua","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Institute of Bone and Joint Diseases Fudan University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martien A. 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