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The properties of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) and penetration enhancers play a deciding role in the inner ear drug delivery of NPs across the round window membrane (RWM). Thus, PLGA nano-based systems with a variety of particle sizes and surface chemistries and those combined with cell-penetrating peptides (CPPs) as penetration enhancers were devised to explore their impact on the cochlear drug delivery in vivo. First, we demonstrated that the properties of NPs dictated the extent of NP cochlear entry by near-infrared fluorescence imaging. NPs with the sizes of 150 and 300 nm had faster entry than that of 80 nm NPs. At 0.5 h, among the NPs unmodified and modified with chitosan (CS), poloxamer 407 (P407) and methoxy polyethylene glycol, CS-PLGA-NPs (positive surface charge) carried payload to the cochlea fastest, whereas P407-PLGA-NPs (surface hydrophilicity) showed the greatest distribution in the cochlea at 24 h. Compared to other CPPs (TAT, penetratin and poly(arginine)8), low molecular weight protamine (LMWP) performed an outstanding enhanced NP cellular uptake in HEI-OC1 cells and cochlear entry. More importantly, NPs with optimized properties and CPPs may be combined to improve RWM penetration. For the first time, we confirmed that the combination of P407-PLGA-NPs (mean diameter: 100–200 nm) and LMWP provided a synergistic enhancement in NP entry to the organ of Corti and stria vascularis without inducing pathological alteration of cochlear tissues and RWM. Taken together, we propose an effective PLGA nano-based strategy for enhanced drug delivery to the inner ear tissues that combines hydrophilic molecule-modified NPs and CPPs, ultimately opening an avenue for superior inner ear therapy.