Local cochlear delivery of berberine chloride hydrate via an injectable photo-crosslinked hydrogel for treating diabetes- induced hearing loss.

Drug delivery to the inner ear remains a major hurdle to effective therapy, underscoring the importance of precision-based delivery strategies. Diabetes-induced hearing loss (DHL) is a debilitating condition with limited therapeutic options, primarily driven by oxidative stress and microvascular damage in the cochlea. Current treatments are ineffective, highlighting the paramount need for novel strategies. Gelatin methacryloyl (GelMA) hydrogels, owing to their biocompatibility and tunable physicochemical properties, enables in situ crosslinking using ultraviolet (UV) light for precise localization of therapeutic agents. Berberine, renowned for its antioxidant and anti-inflammatory efficacy, has shown potential in mitigating diabetes-related complications and certain types of hearing loss. However, its limited solubility and poor permeability across the blood-labyrinth barrier (BLB) hinder its systemic efficacy. To circumvent this, we designed a localized, injectable, and photo-crosslinked GelMA conjugated berberine chloride hydrate (BCH) hydrogel for sustained cochlear drug delivery. Our results demonstrated that GelMA-BCH hydrogel exhibited excellent biocompatibility, robust adhesion, and prolonged cochlear drug retention, enhancing therapeutic outcomes. Liquid chromatography-mass spectrometry (LC-MS) confirmed higher perilymph BCH concentration following localized GelMA-BCH hydrogel administration compared to systemic free BCH delivery. In streptozotocin (STZ)-induced diabetic mice, GelMA-BCH hydrogel treatment demonstrated significant recovery in auditory function, with improved auditory brainstem responses (ABR) thresholds compared to untreated diabetic controls. Morphological analysis revealed preserved cochlear integrity, particularly through protection of outer hair cells (OHCs) and cochlear synapses. In vitro, GelMA-BCH protected auditory House Ear Institute-Organ of Corti 1 (HEI-OC1) cells by reducing STZ-induced oxidative stress, thereby suppressing inflammatory cytokines and mitochondrial-mediated apoptosis, leading to markedly improved cellular resilience. These findings reinforce the potential application of GelMA-BCH hydrogel as a targeted, bioactive therapeutic strategy for cochlear protection in DHL, offering a novel strategy for future clinical translation and address the urgent unmet need in otology and regenerative medicine.