Dorsal root ganglion-targeted analgesic delivery for effective relief of neuropathic pain

Neuropathic pain is a devastating experience for patients and its treatment remains challenging. Dorsal root ganglion (DRG) is currently an important therapeutic target and DRG-targeted analgesic delivery through systemic injection is however not reported. Herein, a disintegrin and metalloproteinase protein 8 (ADAM8), a membrane-anchored protein primarily recognized as a cancer biomarker, is found to be de novo and persistently upregulated in the DRG neurons in spared nerve injury (SNI) and chemotherapy-induced neuropathic pain (CINP), two neuropathic pain models with distinct mechanisms. We thus designed a DRG-targeted delivery strategy using lipid nanoparticles (LNPs), aiming to effectively deliver conventional analgesics to the DRG to improve analgesic effect through blocking pain signal transduction from the periphery to central nervous system. In vitro and in vivo results revealed that LNPs extended the duration of action of the free analgesic from less than 6 h to more than 24 h and particularly, showed therapeutic superiority over conventional liposomes, achieved by their good structural stability for a more sustained release kinetics. After functionalized with a specific ADAM8 inhibitory peptide, the intravenously injected LNPs facilitated analgesic accumulation in the DRG in SNI and CINP. As a result, the LNPs significantly improved the intensity of action for pain relief in a single or repeated treatments, which ultimately relieved pain-related psychiatric comorbidities, while not causing latent systemic toxicities. To our best knowledge, it is the first example of nanoparticles-based DRG-targeted delivery strategy through systemic injection in treating neuropathic pain.