Abstract

Osteoarthritis (OA) is a prevalent degenerative joint disease affecting major joints, causing pain and functional impairment due to cartilage degeneration and osteophyte formation. Current treatments have significant limitations. Mesenchymal stromal cell (MSC)-based therapy is advantageous for its regenerative and immunomodulatory properties, with the infrapatellar fat pad (IPFP) being a reliable MSC source involved in knee osteoarthritis (KOA) progression. MSC-derived exosomes (MSCs-Exo) are key for therapeutic efficacy through paracrine actions but face rapid clearance by the reticuloendothelial system. Sustained release drug delivery systems based on biodegradable biomaterials could enhance MSCs-Exo retention and control their release, promoting tissue repair. Previous studies indicate that wogonin, a natural flavonoid from Scutellaria baicalensis, can stimulate MSCs and be associated with enhanced therapeutic efficacy of MSCs-Exo. This study develops a thermosensitive hydrogel delivery system for intra-articular injection, incorporating IFP-MSCs-Exo (Gel@MSC IPFP -Exo) and wogonin (Gel@Wogonin-MSC IPFP -Exo). Thermosensitive gelation aligned with pathological joint hyperthermia enabled intelligent, sustained exosome delivery. Gel@Wogonin-MSC IPFP -Exo significantly enhanced chondrocyte proliferation and migration while inhibiting inflammatory apoptosis. In vivo, the hydrogel prolonged localized retention to 28 days, doubling the <14-day clearance of free exosomes, resulting in statistically superior cartilage repair and lower OARSI scores. Furthermore, the system profoundly modulated the synovial microenvironment by significantly downregulating iNOS/IL-1β and upregulating Arg-1. These findings highlight the potential of wogonin-stimulated MSC-derived exosomes within a thermosensitive hydrogel to improve OA treatment outcomes; while this study validates the improved therapeutic outcomes of this composite system, the mechanisms underlying cartilage degeneration a