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The blood labyrinth barrier (BLB) hinders systemic drug delivery to the inner ear. This study applied a retro\u2010auricular round window membrane (RWM) method to bypass the BLB, enabling the transport of macromolecular proteins into the inner ear. Pigment epithelium\u2010derived factor (PEDF), which has anti\u2010inflammatory and neuroprotective properties, is conjugated to a prestin\u2010targeting peptide 2 (PrTP2) using N\u2010succinimidyl\u20103\u2010maleimidopropionate (SMP) to form PrTP2\u2010SMP\/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\u2010linked 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\u2010like receptor protein 3 (NLRP3)\u2010apoptosis\u2010associated speck\u2010like protein containing a CARD (ASC) \u2013 cysteinyl aspartate specific proteinase (Caspase\u20101) pathway and PrTP2\u2010SMP\/PEDF alleviates the inflammatory response by inhibiting pyroptosis. Toxicity analysis indicates no adverse effects, suggesting that PrTP2\u2010SMP\/PEDF has a promising therapeutic prospective for NIHL.<\/jats:p>","DOI":"10.1002\/adhm.202403537","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T02:09:46Z","timestamp":1737943786000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A OHCs\u2010Targeted Strategy for PEDF Delivery in Noise\u2010Induced Hearing Loss"],"prefix":"10.1002","volume":"14","author":[{"given":"Zeqi","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology\u2010Head and Neck Surgery Affiliated Hospital of Xuzhou Medical University  Xuzhou 221002 P. R. China"},{"name":"Artificial Auditory Laboratory of Jiangsu Province Xuzhou Medical University  Xuzhou 221002 P. R. China"},{"name":"Institute of Audiology and Balance Science Xuzhou Medical University  Xuzhou 221002 P. R. 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