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

ABSTRACT 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.