Extended osteoarthritis pain relief with neosaxitoxin using alginate-core polymeric microparticles.

Osteoarthritis (OA) is a leading cause of chronic pain, affecting millions worldwide. Conventional pharmacological treatments provide only short-term relief and pose risks with long-term use, highlighting the need for safer, sustained analgesic strategies. Voltage-gated sodium channels (NaV), particularly NaV1.7, are key mediators of OA pain and represent a promising therapeutic target. Neosaxitoxin (NSTX), a potent site-1 sodium channel blocker (S1SCB), exhibits high affinity for NaV1.7. Clinical studies demonstrate that subcutaneous administration of NSTX can safely block sensory pain in healthy individuals, but its anesthetic effect is short-lived, limiting its clinical utility for OA. Here, we report the first use of NSTX for OA pain relief with a local intra-articular (IA) delivery approach. A low dose (10 pg) produced effective pain relief in a post-traumatic OA mouse model, as assessed by knee hyperalgesia testing. However, the effect persisted for only a few hours even with a 100-fold higher dose, highlighting the need for sustained delivery. To prolong this short-lived pain relief and overcome the challenges of encapsulating small, hydrophilic S1SCBs like NSTX, we developed a sustained-release platform using alginate-poly(lactic-co-glycolic acid) microparticles (AlgPLGA-MPs). Incorporation of a negatively charged alginate core in the inner aqueous phase enhanced NSTX encapsulation through electrostatic interactions and minimized burst release. IA injection of NSTX encapsulated AlgPLGA-MP in a murine OA model produced significant pain relief for up to one week. To further prolong joint residence time, the microparticle surface was functionalized with cationic avidin (AvAlgPLGA-MP) that reversed the net surface charge from anionic to cationic. This modification promoted electrostatic binding to negatively charged synovial matrix components and prolonged intra-joint retention time, while maintaining biocompatibility. Together, these results establish NSTX as a highly potent analgesic for chronic OA pain and present alginate-core PLGA microparticles as a safe and effective sustained-release platform. This delivery system holds broad translational potential for other small, hydrophilic analgesics and therapeutic agents.