Extracellular vesicles in sensorineural hearing loss: mechanisms, biomarkers, and therapeutic frontiers

Sensorineural hearing loss (SNHL) is the most common sensory disorder worldwide, affecting more than 1.5 billion people, yet no approved pharmacological treatment exists beyond hearing aids and cochlear implants. Extracellular vesicles (EVs) are nanoscale lipid bilayer particles secreted by nearly all cell types that carry bioactive cargo such as microRNAs, proteins, and lipids, and they have emerged as key mediators of intercellular communication in the inner ear. Over the past five years, rapidly accumulating evidence has revealed a dual role for EVs in the cochlea: endogenous EVs, through cargo such as heat shock protein 70 (HSP70), protect hair cells under stress conditions, whereas pathological EVs arising from noise exposure, cisplatin treatment, or vestibular schwannoma propagate injury signals. Meanwhile, microRNAs and proteins carried by circulating EVs in serum, plasma, and perilymph have shown promise as liquid biopsy biomarkers in sudden sensorineural hearing loss, cisplatin-related ototoxicity, and hereditary hearing impairment. The largest body of preclinical evidence supports EVs derived from mesenchymal stem cells (MSC EVs) as a cell-free therapeutic approach that alleviates cochlear damage caused by cisplatin, aminoglycosides, noise trauma, and ischemia and reperfusion injury by suppressing apoptosis, reducing inflammation, and enhancing autophagy. Engineering strategies, including EV-mediated CRISPR Cas9 gene editing and hybrid vectors combining exosomes with adeno-associated virus (AAV), further expand the therapeutic toolkit for hereditary hearing loss. This review comprehensively summarizes the biogenesis and physiological functions of inner ear EVs, their pathological roles in hearing loss, their prospects as biomarkers, and the translational path from preclinical EV therapy to the earliest trials in humans, while discussing key bottlenecks and future directions in this field.