A Novel Thermosensitive Curcumin-Loaded Hydrogel That Modulates Macrophage M1/M2 Polarization for Osteoarthritis Therapy.

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation, inflammation, and pain, for which conventional systemic therapies often lack sustained efficacy. Therefore, localized delivery platforms that provide both sustained release and therapeutic activity are urgently needed. We developed a thermosensitive injectable hydrogel-hydroxybutyl chitosan (HBC)-that transitions from a sol to a gel at physiological temperature (37 °C). Curcumin, a natural anti-inflammatory compound with poor bioavailability, was loaded to create a composite hydrogel system (Cur@HBC). HBC exhibited excellent injectability, stability, and biocompatibility. Cur@HBC enabled sustained release of curcumin and significantly attenuated OA progression in vivo, as evidenced by reduced cartilage degradation, decreased expression of MMP13 and pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), improved Collagen II retention, and recovery of cartilage function. Mechanistically, curcumin inhibited chondrocyte apoptosis and promoted macrophage polarization toward the M2 phenotype. This study presents a dual-functional hydrogel platform that combines thermosensitive mechanical support with sustained anti-inflammatory drug delivery. The injectable Cur@HBC hydrogel shows great promise as a localized OA therapy, with the potential to improve joint function.