A precision therapy paradigm for noise-induced hearing loss: integrating transcriptome-guided drug repurposing with in situ hydrogel delivery

Abstract

Noise-induced hearing loss (NIHL) constitutes a growing global health burden, yet effective pharmacological interventions remain elusive. Current therapeutic development is severely constrained by two critical bottlenecks: the lack of rationally identified molecular targets and the absence of dosage forms tailored to the physiological barriers of the inner ear. Addressing these limitations, we propose an integrated precision therapy strategy. First, to overcome the unpredictability of drug selection, we employed a transcriptome-guided network pharmacology approach, which rationally identified GBR-12935 – a dopamine transporter (DAT) inhibitor – as a potent candidate capable of reversing the pathological gene signature of noise injury. However, as a central nervous system (CNS)-active agent, the clinical translation of GBR-12935 is hindered by its rapid clearance from the middle ear and the risk of off-target CNS effects due to the ear's anatomical proximity to the brain. To resolve this delivery dilemma, we engineered an injectable, in situ forming hydrogel specifically designed for sustained intratympanic administration. This biomaterial platform effectively prolongs drug residence time in the round window niche while minimizing systemic leakage, thereby maximizing local cochlear bioavailability and mitigating potential neurotoxicity. In a mouse model of severe acoustic trauma (110 dB SPL), the hydrogel-mediated delivery significantly outperformed free drug administration. Quantitative immunofluorescence revealed that this localized intervention not only prevented the loss of cochlear ribbon synapses but, crucially, inhibited the pathological enlargement and aggregation of surviving ribbons, maintaining their morphological stability against excitotoxic edema. This structural preservation translated into robust functional recovery, evidenced by attenuated Auditory Brainstem Response (ABR) threshold shifts (15 dB rescue at 24 kHz, P < 0.01 vs. noise). Collectively, our study establishes a closed-loop paradigm combining computational prediction with rational biomaterial design, providing a potent and safe non-steroidal auditory protection strategy for addressing cochlear synaptopathy.