ROS-responsive nanoplatform-mediated targeted intranasal delivery of Piezo2 siRNA for the treatment of trigeminal...

Trigeminal neuralgia (TN) is one of the most severe neuropathic pain conditions, yet current pharmacological treatments are hindered by low bioavailability, systemic toxicity, and drug resistance. The mechanosensitive ion channel Piezo2 has been identified as a key mediator of orofacial mechanical allodynia in TN, making it a highly attractive but as yet clinically untargeted therapeutic target. To address this critical gap, we developed RLPSe nanoparticles, a microenvironment-adaptive nanoplatform composed of a polyvinylamine (PVAm)-L44 copolymer crosslinked via diselenide bonds and conjugated with rabies virus glycoprotein 29 (RVG29). The diselenide bond confers oxidative stress responsiveness, while RVG29 enables specific neuronal targeting. In vitro studies demonstrated that RLPSe nanoparticles exhibited good biocompatibility, oxidative stress responsiveness, and neuronal targeting efficiency; they effectively scavenged intracellular reactive oxygen species and delivered siRNA to knock down Piezo2 expression in neurons. Following intranasal administration in vivo, RLPSe nanoparticles were successfully internalized by trigeminal ganglion cells. Notably, this was associated with reduced neuronal activation in central pain-related regions, including the spinal trigeminal nucleus caudalis and primary somatosensory cortex. Collectively, this study presents a non-invasive, microenvironment-adaptive gene silencing strategy that combines intranasal delivery, oxidative stress responsiveness, and Piezo2 knockdown, representing a promising approach for further investigation in the context of trigeminal neuralgia.