A Baicalin-Based Functional Polymer in Dynamic Reversible Networks Alleviates Osteoarthritis by Cellular Interactions

Osteoarthritis (OA) is increasingly recognized as a whole-organ disease predominantly affecting the elderly, characterized by typical alterations in subchondral bone and cartilage, along with recurrent synovial inflammation. Despite the availability of various therapeutics and medications, a complete resolution of OA remains elusive. In this study, novel functional hydrogels are developed by integrating natural bioactive molecules for OA treatment. Specifically, baicalin (Bai) is combined with 2-hydroxyethyl acrylate (HEA) to form a polymerizable monomer (HEA-Bai) through esterification, which is subjected to reversible addition-fragmentation chain transfer (RAFT) polymerization to produce Bai-based polymer (P_m). These macromolecules are incorporated into Schiff-base hydrogels, which demonstrate excellent mechanical properties and self-healing performance. Notably, the Bai-based formulations are taken up by fibroblast-like synoviocytes (FLSs), where they regulate glycolysis. Mechanistically, inhibition of yes-associated protein 1 (YAP1) by the formulations suppressed the FLSs glycolysis and reduced the secretion of inflammatory factors, including interleukin 1β (IL-1β), IL-6, and IL-8. Furthermore, the functional hydrogel (AG-P_m)-OC, severing as a lubricant and nutrient, prolonged joint retention of Bai, thereby reducing cartilage degradation and synovial inflammation. Meanwhile, (AG-P_m)-OC alleviated joint pain by targeting the YAP1 signaling and inhibiting macrophage recruitment and polarization. Taken together, this flavonoid-based injectable hydrogel exhibits enhanced biocompatibility and efficacy against OA.