pH-responsive Zn2+-coordinated gellan gum/γ-polyglutamic acid hydrogel microspheres as functional biomaterials for intra-articular delivery: physicochemical design, smart release, and chondroprotective performance in osteoarthritis.

INTRODUCTION: Osteoarthritis (OA) is a degenerative joint disease characterized by progressive degradation of the articular cartilage matrix, pain-related functional impairment, and a paucity of effective disease-modifying therapies. Curculigoside (Cur), a bioactive compound isolated from Curculigo orchioides, possesses anti-inflammatory and tissue-protective properties; however, its direct intra-articular application is hampered by insufficient local retention and limited sustained action.

METHODS: We developed a Zn2+-coordinated pH-responsive hydrogel microsphere delivery system (PGG-Zn@Cur) based on gellan gum (GG) and γ-polyglutamic acid (γ-PGA) to enable localized intra-articular delivery of Cur. Its cytocompatibility and chondroprotective effects were evaluated in IL-1β-stimulated chondrocytes. Transcriptomic analysis was further performed to investigate the potential molecular mechanisms underlying its therapeutic effects.

RESULTS: PGG-Zn@Cur exhibited excellent cytocompatibility and restored cartilage matrix metabolic homeostasis in IL-1β-stimulated chondrocytes, as evidenced by increased COL2A1 and ACAN expression and reduced MMP13, ADAMTS5, and iNOS levels. Transcriptomic analysis implicated PI3K-AKT signaling and apoptosis-related pathways in the chondroprotective effects mediated by PGG-Zn@Cur. Mechanistically, PGG-Zn@Cur suppressed PI3K-AKT pathway hyperactivation, downregulated Cleaved Caspase-3 and Bax expression, attenuated chondrocyte apoptosis, and alleviated cartilage degeneration.

DISCUSSION: These findings establish PGG-Zn@Cur as a microenvironment-responsive intra-articular platform that maintains cartilage matrix homeostasis and alleviates PI3K-AKT-associated apoptosis-related responses, offering a promising strategy for disease-modifying OA therapy.