Injectable Regenerated Silk Fibroin Micro/Nanosphere with Enhanced Permeability and Stability for Osteoarthritis Therapy

Abstract In the therapy of early‐stage osteoarthritis, to accomplish full infiltration of subchondral bone and cartilage, and to target osteoclast and chondrocyte simultaneously remain challenges in biomaterials design. Herein, a novel hierarchical drug delivery system is introduced, with micrometer‐scale outer layer spheres composed of regenerated silk fibroin, characterized by connected porous structure through the n‐butanol 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‐enriched silk fibroin nanoparticles, stabilized through chemical cross‐linking, which encapsulate isoliquiritin derived from Glycyrrhiza uralensis. These nanoparticles facilitate complete penetration of the cartilage extracellular matrix, exhibit pH‐responsive 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.