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

Abstract 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.