Ultrasound-Triggered NO Release to Promote Axonal Regeneration for Noise-Induced Hearing Loss Therapy

Intense noise poses a threat to spiral ganglion neurons (SGNs) in the inner ear, often resulting in limited axonal regeneration during noise injury and leading to noise-induced hearing loss (NIHL). Here, we propose an ultrasound-triggered nitric oxide (NO) release to enhance the sprouting and regeneration of injured axons in SGNs. We developed hollow silicon nanoparticles to load nitrosylated N-acetylcysteine, producing HMSN-SNO, which effectively protects NO from external interferences. Utilizing low-intensity ultrasound stimulation with bone penetration, we achieve the controlled release of NO from HMSN-SNO within the cochlea. In mice with NIHL, a rapid and extensive loss of synaptic connections between hair cells and SGNs is observed within 24 h after exposure to excessive noise. However, this loss could be reversed with the combined treatment, resulting in a hearing functional recovery from 83.57 to 65.00 dB SPL. This positive outcome is attributed to the multifunctional effects of HMSN-SNO, wherein they scavenge reactive oxygen species (ROS) to reverse the pathological microenvironment and simultaneously upregulate the CREB/BDNF/EGR1 signaling pathway, thereby enhancing neuroplasticity and promoting the regeneration of neuronal axons. These findings underscore the potential of nanomedicine for neuroplasticity modulation, which holds promise for advancing both basic research and the further treatment of neurological diseases.