The quest to restore hearing and balance function has long been a central challenge in medicine, particularly for genetic forms of inner ear disorders that have no effective cure. While treatments such as hearing aids and cochlear implants provide significant benefit, they do not address the underlying biological cause. Gene therapy, which aims to deliver functional genes to correct genetic defects or protect delicate sensory cells, represents a paradigm-shifting therapeutic approach.
Here, the review article systematically analyzes the advancements in AAV-mediated gene therapy for the inner ear. AAV vectors have emerged as the leading platform due to their favorable safety profile, ability to transduce non-dividing cells, and potential for long-term gene expression. Significant progress has been made in engineering novel AAV serotypes and synthetic capsids with enhanced tropism for specific inner ear cell types, such as hair cells and spiral ganglion neurons. Furthermore, refined surgical delivery methods, including round window membrane injection and cochleostomy, are being optimized to achieve widespread transduction while preserving fragile auditory structures.
However, significant hurdles remain in translating these therapies to the clinic. Key challenges include the limited carrying capacity of AAV vectors, which restricts the size of therapeutic genes that can be delivered; pre-existing immunity to common AAV serotypes in the human population; potential inflammatory responses; and the need for precise, early intervention before irreversible cellular degeneration occurs. The heterogeneity of genetic hearing loss, with its wide variety of underlying mutations, demands the development of personalized therapeutic strategies. This work provides a crucial roadmap for the field, emphasizing the integration of next-generation vector design, novel therapeutic targets (including gene editing), and innovative delivery systems. The article, entitled “AAV-Mediated Gene Therapy for the Inner Ear: Progress, Challenges, and Future Directions” was published on ENT Discovery (published on Dec. 31, 2025).