Nanocomposite hydrogel acupoint therapy for sustained pregabalin delivery and long-term neuropathic pain relief

Neuropathic pain (NP) presents significant management challenges due to the limited efficacy and adverse effects associated with current therapeutic options. In this study, we present an innovative nanocomposite hydrogel designed for acupoint administration (PG@PLGA-gels) that synergistically combines nanomedicine with traditional acupuncture principles. This system is engineered by incorporating pregabalin (PG)-loaded poly (lactic-co-glycolic acid) nanoparticles into a chitosan/β-glycerophosphate thermosensitive hydrogel, facilitating minimally invasive administration at the Huantiao (GB30) acupoint. Compared to PG solution, PG@PLGA-gels exhibited a sustained drug release profile, extending over 12 days, with an initial release of 46.44% within the first 24 h, and increased systemic exposure by a factor of 2.6-fold. Following acupoint injection, plasma PG concentrations reached their peaked at 16 h (7985.94 ± 96.19 ng/mL) and remained detectable for up to 288 h, whereas PG solution peaked at 4 h (4928.33 ± 124.71 ng/mL) and declined to near-baseline levels by 192 h. In rat models of paclitaxel-induced neuropathy and chronic constriction injury, acupoint administration of PG@PLGA-gels significantly mitigates mechanical and cold allodynia from day 8 to day 20, while no obvious sedation-related behaviors were observed. Transcriptomic analysis identified treatment-associated changes in spinal cord gene expression profiles, with enrichment in pathways related to neuronal structure, synaptic organization, excitatory signaling, and neuroendocrine regulation. Together, these results support PG@PLGA-gels as an acupoint nanomedicine platform that combines controlled drug delivery with acupoint-based modulation to achieve prolonged analgesia with minimized adverse effects.