Approximately 360 million people—5% of the worlds population—suffer from disabling hearing impairment resulting from outer hair cells (OHCs) dysfunction or loss, according to the World Health Organization.Effective delivery of therapeutic agents into the inner ear cell is challenging due to formidable physiological and anatomic barriers.First, the feasibility of poly (d,l-lactide-co-giycolide acid) (PLGA) nanoparticles (NPs) for carrying single or compound drugs traversing the round window membrane (RWM) was examined after inner ear administration.Then, different surface-modified PLGA NPs were developed to evaluate their potential for optimizing delivery to the inner ear and OHCs.Our results indicated that PLGA NPs could compensate for the negative molecule properties of the cargo and had great potential in transporting hydrophilic and hydrophobic drugs simultaneously across the RWM into the cochlea, thus resulting in enhanced local bioavailability of the encapsulated drugs in the inner ear.More importantly, we found that various surface-modified PLGA NPs were distributed in the OHCs and P407-modified PLGA NPs showed thebestcellular uptake ability.These findings suggest that the nanomedicine strategy to deliver the drug into the inner ear across RWM will provide a platform for a more efficient treatment for inner ear disorders.