A OHCs‐Targeted Strategy for PEDF Delivery in Noise‐Induced Hearing Loss

Abstract Noise‐induced hearing loss (NIHL) results from prolonged exposure to intense noise, causing damage to sensory outer hair cells (OHCs) and spiral ganglion neurons (SGNs). The blood labyrinth barrier (BLB) hinders systemic drug delivery to the inner ear. This study applied a retro‐auricular round window membrane (RWM) method to bypass the BLB, enabling the transport of macromolecular proteins into the inner ear. Pigment epithelium‐derived factor (PEDF), which has anti‐inflammatory and neuroprotective properties, is conjugated to a prestin‐targeting peptide 2 (PrTP2) using N‐succinimidyl‐3‐maleimidopropionate (SMP) to form PrTP2‐SMP/PEDF. This compound specifically targeted Prestin and accumulated around OHCs for sustained release, effectively reducing OHC and SGN loss. Functional and structural tests, including auditory brainstem response (ABR), confocal microscopy, and scanning electron microscopy (SEM), revealed significant hearing restoration and cellular protection. Additionally, the results of enzyme‐linked immunosorbent assay (ELISA), Annexin V and propidium iodide (PI) staining and immunoblotting show that noise exposure may induce pyroptosis in the cochlea by activating the NOD‐like receptor protein 3 (NLRP3)‐apoptosis‐associated speck‐like protein containing a CARD (ASC) – cysteinyl aspartate specific proteinase (Caspase‐1) pathway and PrTP2‐SMP/PEDF alleviates the inflammatory response by inhibiting pyroptosis. Toxicity analysis indicates no adverse effects, suggesting that PrTP2‐SMP/PEDF has a promising therapeutic prospective for NIHL.