Zwitterion‐Lubricated Hydrogel Microspheres Encapsulated with Metformin Ameliorate Age‐Associated Osteoarthritis

Chondrocyte senescence and reduced lubrication play pivotal roles in the pathogenesis of age-related osteoarthritis (OA). In the present study, highly lubricated and drug-loaded hydrogel microspheres are designed and fabricated through the radical polymerization of sulfobetaine (SB)-modified hyaluronic acid methacrylate using microfluidic technology. The copolymer contains a large number of SB and carboxyl groups that can provide a high degree of lubrication through hydration and form electrostatic loading interactions with metformin (Met@SBHA), producing a high drug load for anti-chondrocyte senescence. Mechanical, tribological, and drug release analyses demonstrated enhanced lubricative properties and prolonged drug dissemination of the Met@SBHA microspheres. RNA sequencing (RNA-seq) analysis, network pharmacology, and in vitro assays revealed the extraordinary capacity of Met@SBHA to combat chondrocyte senescence. Additionally, inducible nitric oxide synthase (iNOS) has been identified as a promising protein modulated by Met in senescent chondrocytes, thereby exerting a significant influence on the iNOS/ONOO-/P53 pathway. Notably, the intra-articular administration of Met@SBHA in aged mice ameliorated cartilage senescence and OA pathogenesis. Based on the findings of this study, Met@SBHA emerges as an innovative and promising strategy in tackling age-related OA serving the dual function of enhancing joint lubrication and mitigating cartilage senescence.