Intranasal Approach of Thermoresponsive Hydrogel Delivering Dexamethasone to the Inner Ear for Treating Hearing Loss

Hearing loss is a widespread global disability, commonly treated using dexamethasone (Dex). However, targeted delivery of Dex to the inner ear remains a significant challenge due to the blood-perilymph barrier (BLB), which limits its therapeutic efficacy. In this study, we aimed to develop a strategy to enhance Dex delivery to the inner ear and improve its treatment outcome by the noninvasive intranasal approach. Also, poly(ethylene glycol) (PEG)─liposomal nanoparticles were used as a drug carrier and loaded with Dex (PLN-Dex). For intranasal delivery, a thermosensitive hydrogel was fabricated by methylcellulose. The PLN-Dex nanocomposite was incorporated into the hydrogel to obtain PLN-Dex@Gel. PLN-Dex@Gel could be administrated intranasally and their transport pathway from olfactory mucosa to the cochlea was explored. In vivo magnetic resonance and fluorescence microscopy showed that drugs delivery into the olfactory mucosa reached the inner ear by dispersive transport via the brain. Interestingly, we found that beyond the cochlear duct, the cochlear axis may serve as a crucial pathway for the transportation of drugs from the brain to the inner ear. In guinea pig models of LPS-induced and noise-induced hearing loss, intranasal PLN-Dex@Gel treatment significantly reduced auditory brainstem response thresholds, ameliorated cochlear blood flow, and protected hair cells and synapses. Our findings underscore the potential of intranasal Dex delivery as a noninvasive and effective strategy for treating hearing loss. The target drug delivery to the inner ear, combined with the enhanced formulation of Dex-loaded liposomal hydrogels, offers promising prospects for future research in the treatment of inner ear disorders, with potential for clinical translation. This study expands the understanding of delivery route from nose to inner ear and suggests a method for utilizing intranasal administration as a strategy for treating hearing loss.