Charge‐Guided Deep Cartilage Targeting Carriers for Nav1.7‐Mediated Osteoarthritis Treatment via Simultaneous Pain Management and Cartilage Protection

Abstract Osteoarthritis (OA) is a degenerative joint disease characterized by chronic pain and cartilage degeneration, with a lack of effective molecular pathway‐targeted therapies. The voltage‐gated sodium channel Nav1.7 is identified as a promising therapeutic target due to its dual role in pain transmission and regulation of chondrocyte metabolism. However, inflammation‐induced mitochondrial dysfunction significantly diminishes the efficacy of the Nav1.7 inhibitor PF‐04856264 (PF), and Nav1.7 inhibitor shows dose‐dependent variations in its analgesic and chondroprotective effects. To address this limitation, an intra‐articular sustained‐release platform is developed that integrates methacrylic acid hyaluronic acid‐based microspheres with cationic liposomes, forming a dual release platform. This platform enhances drug retention within the joint and improves cartilage penetration by overcoming electrostatic shielding. In vitro studies demonstrated that alanyl‐glutamine (AG) effectively alleviates mitochondrial oxidative stress, restores energy metabolism homeostasis, and enhances PF‐mediated calcium influx and cartilage metabolism regulation via ATP production. In a sodium iodoacetate‐induced OA model, the combined administration of PF and AG significantly mitigated cartilage degradation and improved joint function. Moreover, the responsive release profile of PF enables on‐demand analgesia. This target strategy, which combines pain relief with cartilage protection through personalized drug delivery, provides a novel therapeutic approach for OA by simultaneously modulating neuronal and chondrocyte functions.