PLGA Nanoparticle-Based Optogenetic Control of the NLRP3 Inflammasome for Neuropathic Pain Relief

Abstract

Neuropathic pain is a chronic disorder with diverse etiologies and heterogeneous symptoms, and current pharmacological treatments remain insufficient. Growing evidence suggests that the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is a major mediator of neuroinflammation and central sensitization, yet therapeutic strategies for its precise modulation are still limited. This study investigated the role of NLRP3 in neuropathic pain and evaluated a novel therapeutic approach. A spared nerve injury (SNI) mouse model was established, and plasmid-loaded poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) designed to regulate NLRP3 expression were administered intrathecally. Optogenetic stimulation was applied to achieve spatiotemporal control of inflammasome activity. Behavioral assessments were established by measuring mechanical allodynia and hypersensitivity. The combined nanoparticle delivery and optogenetic stimulation significantly suppressed NLRP3 activation, reduced pro-inflammatory cytokine secretion, and alleviated pain hypersensitivity in SNI mice. These findings highlight the pivotal contribution of the NLRP3 inflammasome to neuropathic pain and demonstrate the potential of integrating nanotechnology with optogenetics as a non-pharmacological, molecularly targeted therapeutic strategy.