Engineered RVG-exosomes-mediated delivery of siRNAs targeting NMDAR alleviates orofacial neuropathic pain by suppressing central sensitivity.

Orofacial neuropathic pain (NP) is a common complication in oral clinical practice that severely affects quality of life. However, NP does not currently receive effective medications. Engineered exosomes have great potential as drug delivery systems for treating diseases. Here, patch clamp techniques showed that the deficiency of N-methyl-D-aspartic acid receptor (NMDAR) subunits 2A and 2B reversed the spontaneous excitatory postsynaptic current (sEPSC) frequency and neuronal excitability in the spinal trigeminal nucleus caudalis (SpVc) after injury, which is an effective therapeutic target for NP. Hence, we successfully employed exosomes (EXOs) modified with the nervous system-specific rabies virus glycoprotein (RVG) peptide, which exhibited excellent targeting ability towards N2a-Neuro cells and SpVc tissue. RVG-EXOs loaded with siRNAs of NR2A/B efficiently targeted SpVc neurons, further reducing neuronal excitability and relieving the orofacial NP. Taken together, our study investigated the role of NR2A/B in central nociceptive sensitization and suggested that RVG-EXOs-mediated delivery of siRNAs targeting NR2A and NR2B was effective for orofacial NP treatment. PERSPECTIVE: This study investigated the crucial role of NMDAR in central sensitization of the SpVc after nerve injury. In this study, we innovatively explored a central targeted drug delivery system based on engineered RVG-EXOs, providing a basis for targeted minimally invasive treatments of orofacial NP.