Motor Neuron‐Specific Membrane Depolarization of Transected Peripheral Nerves by Upconversion Nanoparticle‐Mediated Optogenetics

Abstract It remains a fundamental challenge to administer guided regeneration and functional recovery of peripheral nerves after the complete transection. Herein, a new concept to specifically depolarize the membranes of the target acetylcholinergic motor neurons by near infrared (NIR) laser‐triggered optogenetics for promoted functional reconnection of transected peripheral nerves is reported. The approach features the anchoring of acetylcholine‐modified upconversion nanoparticles (UCNP) onto the acetylcholine receptors on the postsynaptic membrane and selective infection of the motor neural cells with adeno‐associated virus loading channelrhodopsin 2 (ChR2). The upconversion fluorescence mediated by UCNP can activate ChR2 protein for membrane depolarization of the acetylcholinergic motor neurons. It induces a cascade of events, including axonal regeneration, Schwann cells remyelination, brain‐derived neurotrophic factor expression enhancement, and the remodeling of neuromuscular junctions (NMJ) from muscle denervation, which leads to promoted functional reconnection of the injured peripheral nerves. The results of behavioral and electrophysiological experiments further verify the functional recovery of transected peripheral nerves by the approach. The UCNP‐mediated optogenetic strategy of minimally invasive, precisely guided, and functional reconnection of injured nerves shall bring great benefits to both fundamental research and translational development in neural regenerative medicine.