Rabies Virus Glycoprotein-Decorated Liposomes in Thermosensitive Nasal Spray Gels: Facilitating Retrograde Neural Transport for Targeted Trigeminal Neuralgia Therapy

Clinical management of trigeminal neuralgia (TN) is hindered by poor neural bioavailability and systemic toxicity of oral drugs. While the nasal route offers a direct pathway to target the trigeminal nerve, rapid mucociliary clearance and competition from systemic absorption limit its effectiveness. To address these limitations, this study aimed to develop a biomimetic nasal gel system for targeted drug delivery to the trigeminal nerve. Inspired by the neurotropism of rabies virus, we engineered a thermoresponsive nasal spray gel (OMRLP@NSG). The system utilizes rabies virus glycoprotein (RVG)-modified liposomes coloaded with oxcarbazepine and mecobalamin. The liposomal formulation was specifically chosen to enhance drug stability, facilitate mucosal penetration, and provide a platform for neuron-specific targeting via RVG modification. Upon nasal administration, the OMRLP@NSG transitions from spray to gel, enhancing nasal distribution, mucosal adhesion, and neuron-specific targeting. Pharmacokinetics demonstrated a 3 h earlier <i>T</i>_max and 537.25% higher relative bioavailability in trigeminal nerves versus oral Trileptal. OMRLP@NSG at 1/10th the Trileptal dose achieved comparable trigeminal nerve exposure while reducing off-target site concentrations by 74.18∼92.00% (plasma, brain, liver). Pharmacodynamics showed that the OMRLP@NSG significantly alleviated TN pain in rats, increasing the pain threshold by 3.92-fold over Trileptal. It also normalized the expression of pain-related neuropeptides (substance P and β-endorphin) to 112.05 and 98.81% of normal levels, respectively. Mechanistically, it suppressed P2 × 7R/NLRP3 inflammasome activation, downregulating IL-1β and TNF-α, thereby reducing neuronal damage and promoting remyelination. Additionally, long-term toxicity studies confirmed the favorable <i>in vivo</i> biosafety. This strategy transcends conventional systemic administration paradigms by resolving the tripartite challenge of spatial control, temporal retention, and cellular precision, thereby addressing the critical clinical demand for effective nose-to-brain delivery in trigeminal neuralgia.