Ultrasound-Triggered\nNO Release to Promote Axonal\nRegeneration for Noise-Induced Hearing Loss Therapy

Intense\nnoise poses a threat to spiral ganglion neurons (SGNs)\nin the inner ear, often resulting in limited axonal regeneration during\nnoise injury and leading to noise-induced hearing loss (NIHL). Here,\nwe propose an ultrasound-triggered nitric oxide (NO) release to enhance\nthe sprouting and regeneration of injured axons in SGNs. We developed\nhollow silicon nanoparticles to load nitrosylated N-acetylcysteine,\nproducing HMSN-SNO, which effectively protects NO from external interferences.\nUtilizing low-intensity ultrasound stimulation with bone penetration,\nwe achieve the controlled release of NO from HMSN-SNO within the cochlea.\nIn mice with NIHL, a rapid and extensive loss of synaptic connections\nbetween hair cells and SGNs is observed within 24 h after exposure\nto excessive noise. However, this loss could be reversed with the\ncombined treatment, resulting in a hearing functional recovery from\n83.57 to 65.00 dB SPL. This positive outcome is attributed to the\nmultifunctional effects of HMSN-SNO, wherein they scavenge reactive\noxygen species (ROS) to reverse the pathological microenvironment\nand simultaneously upregulate the CREB/BDNF/EGR1 signaling pathway,\nthereby enhancing neuroplasticity and promoting the regeneration of\nneuronal axons. These findings underscore the potential of nanomedicine\nfor neuroplasticity modulation, which holds promise for advancing\nboth basic research and the further treatment of neurological diseases.