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Herein, a novel hierarchical drug delivery system is introduced, with micrometer\u2010scale outer layer spheres composed of regenerated silk fibroin, characterized by connected porous structure through the n\u2010butanol and regenerated silk fibroin combined emulsion route and freezing method. The design effectively resists clearance from the joint cavity, ensuring stable delivery and prolonged residence time within the joint space. Additionally, the system incorporates phenylboronic acid\u2010enriched silk fibroin nanoparticles, stabilized through chemical cross\u2010linking, which encapsulate isoliquiritin derived from Glycyrrhiza uralensis. These nanoparticles facilitate complete penetration of the cartilage extracellular matrix, exhibit pH\u2010responsive behavior, neutralize reactive oxygen species, and enable controlled drug release, thereby enhancing therapeutic efficacy. The in vitro and in vivo experiments both demonstrate that the composite micro\/nanospheres not only inhibit osteoclastogenesis with bone loss in subchondral bone and osteophyte formation, but also mitigate chondrocytes apoptosis, reduce oxidative stress associated with cartilage degeneration, and ameliorate neuropathic hyperalgesia, with the underlying mechanisms being elucidated. The study indicates that such an injectable strategy combining organic biomaterials with Chinese medicine holds substantial promise for the treatment of early osteoarthritis.<\/jats:p>","DOI":"10.1002\/smll.202405049","type":"journal-article","created":{"date-parts":[[2024,8,5]],"date-time":"2024-08-05T05:44:21Z","timestamp":1722836661000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Injectable Regenerated Silk Fibroin Micro\/Nanosphere with Enhanced Permeability and Stability for Osteoarthritis Therapy"],"prefix":"10.1002","volume":"20","author":[{"given":"Zixiang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Orthopedics Zhongshan Hospital Fudan University State Key Laboratory of Molecular Engineering of Polymers Laboratory of Advanced Materials and Department of Macromolecular Science Fudan University  Shanghai 200032 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