Enhancing Endogenous Hyaluronic Acid in Osteoarthritic Joints with an Anti‐Inflammatory Supramolecular Nanofiber Hydrogel Delivering HAS2 Lentivirus

Abstract Osteoarthritis (OA) management remains challenging because of its intricate pathogenesis. Intra‐articular injections of drugs, such as glucocorticoids and hyaluronic acid (HA), have certain limitations, including the risk of joint infection, pain, and swelling. Hydrogel‐based therapeutic strategies have attracted considerable attention because of their enormous therapeutic potential. Herein, a supramolecular nanofiber hydrogel is developed using dexamethasone sodium phosphate (DexP) as a vector to deliver lentivirus‐encoding hyaluronan synthase 2 (HAS2) (HAS2@DexP‐Gel). During hydrogel degradation, HAS2 lentivirus and DexP molecules are slowly released. Intra‐articular injection of HAS2@DexP‐Gel promotes endogenous HA production and suppresses synovial inflammation. Additionally, HAS2@DexP‐Gel reduces subchondral bone resorption in the anterior cruciate ligament transection‐induced OA mice, attenuates cartilage degeneration, and delays OA progression. HAS2@DexP‐Gel exhibited good biocompatibility both in vitro and in vivo. The therapeutic mechanisms of the HAS2@DexP‐Gel are investigated using single‐cell RNA sequencing. HAS2@DexP‐Gel optimizes the microenvironment of the synovial tissue by modulating the proportion of synovial cell subpopulations and regulating the interactions between synovial fibroblasts and macrophages. The innovative nanofiber hydrogel, HAS2@DexP‐Gel, effectively enhances endogenous HA production while reducing synovial inflammation. This comprehensive approach holds promise for improving joint function, alleviating pain, and slowing OA progression, thereby providing significant benefits to patients.