Collagen II hydrogel-mediated sustained delivery of lacosamide attenuates cartilage degeneration and pain in osteoarthritis

Osteoarthritis (OA) lacks effective disease-modifying therapies. Nav1.7 has recently been identified as a regulator of both chondrocyte metabolism and pain, establishing it as a dual-acting therapeutic target in OA. This study evaluated lacosamide (LCM) as a disease-modifying candidate and developed a cartilage-targeted delivery strategy to enhance its translational potential. Sodium channel inhibitors (carbamazepine, oxcarbazepine, and LCM) were evaluated in primary human OA chondrocytes, cartilage explants, and a murine DMM model with systemic or intra-articular administration. Pain behavior was assessed by von Frey and open-field testing. A collagen II-based thermoresponsive hydrogel was developed for sustained intra-articular delivery, and outcomes were assessed by histology, immunohistochemistry, ELISA, and gene expression analyses. LCM was the most potent inhibitor in suppressing IL-1β-induced catabolism and promoting anabolism in human chondrocytes, showing greater efficacy at lower concentrations than carbamazepine or oxcarbazepine. Systemic LCM reduced cartilage degeneration and pain in murine OA and outperformed carbamazepine at equivalent doses, while intra-articular administration achieved superior protection and analgesia at one-tenth the dose. Mechanistically, LCM increased HSP70 and midkine secretion to drive anabolic and anti-catabolic responses. Sustained delivery via a collagen II-based hydrogel prolonged joint retention and enhanced therapeutic durability. Together with its clinical efficacy in Nav1.7 mutation-related neuropathy, these findings underscore LCM's translational potential as a dual-acting disease-modifying therapy for OA. LCM is a dual-acting Nav1.7 inhibitor that alleviates pain and modifies OA progression. Collagen II-based intra-articular delivery enhances efficacy and supports clinical translation as a noninvasive, non-opioid disease-modifying therapy.