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Herein, a nanomicelle\u2013hydrogel microsphere, characterized by its macrophage-targeted nanosized secondary structure that allows it to accurately bind to M1 macrophages through active endocytosis, is employed for in\u00a0situ sustained macrophage targeting and regulation, and addresses the insufficient osteoarthritis therapeutic efficacy caused by rapid clearance of drug nanocarriers. The 3-dimensional structure of a microsphere can prevent the rapid escape and clearance of a nanomicelle, thus keeping it in joints, while the ligand-guided secondary structure can carry drugs to accurately target and enter M1 macrophages, and release drugs via the transition from hydrophobicity to hydrophilicity of nanomicelles under inflammatory stimulation inside the macrophages. The experiments show that the nanomicelle\u2013hydrogel microsphere can in\u00a0situ sustainably target and regulate M1 macrophages for more than 14 days in joints, and attenuate local \u201ccytokine storm\u201d by continuous M1 macrophage apoptosis promotion and polarization inhibition. This micro\/nano-hydrogel system shows excellent ability to sustainably target and regulate macrophage, realizes the improvement of drug utilization and efficacy inside the macrophage, and thereby can be a potential platform for treating macrophage-related diseases.<\/jats:p>","DOI":"10.34133\/research.0131","type":"journal-article","created":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T13:02:30Z","timestamp":1681304550000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":75,"title":["In Situ Sustained Macrophage-Targeted Nanomicelle\u2013Hydrogel Microspheres for Inhibiting Osteoarthritis"],"prefix":"10.34133","volume":"6","author":[{"given":"XiaoXiao","family":"Li","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, P. R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingchen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, P. R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jielai","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, P. R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yawei","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, P. R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, P. R. 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