Lesion Site-Targeted Microspheres Modulate Nav1.7-Related Signaling for Osteoarthritis Treatment

Osteoarthritis (OA) progression involves cartilage degeneration, inflammation, and pain. Recent evidence suggests that the voltage-gated sodium channel Nav1.7, encoded by Scn9a, links nociceptive signaling with chondrocyte metabolic regulation. Here, we developed an acid-responsive, cartilage-targeted delivery system based on WYRGRL peptide-modified chondroitin sulfate/oxidized hyaluronan composite microspheres loaded with carbamazepine (CBZ), termed CBZ/WCOM, for sustained intra-articular CBZ delivery. In interleukin-1β (IL-1β)-challenged chondrocytes, CBZ/WCOM attenuated inflammatory and catabolic responses, as indicated by reduced Ptgs2, Mmp13, and Adamts5 expression, while partially restoring anabolic markers including Col2a1 and Acan. Mechanistically, CBZ/WCOM reduced sodium current density, modulated Na⁺/Ca²⁺ exchanger (NCX)-associated Ca^{2 +} dynamics, and increased heat shock protein 70 (HSP70) and Midkine secretion, supporting the involvement of Nav1.7-related sodium channel signaling in chondrocyte regulation. In a mouse destabilization of the medial meniscus (DMM) model, intra-articular CBZ/WCOM improved mechanical withdrawal thresholds, reduced pain-related neural remodeling, decreased osteophyte formation, partially preserved joint-space width, improved cartilage matrix phenotype, and ameliorated subchondral bone alterations. By integrating WYRGRL-mediated type II collagen (COL2) targeting with pH-triggered CBZ release, CBZ/WCOM supports lesion-localized drug retention and provides a minimally invasive strategy for local OA therapy.