Zhao Zeqi, Han Zhengzhong, Shao Yudi, Naveena Konduru, Yuan Jintao, Zhou Nan, Wang Caiji, Li Xuanyi, Shi Xi, Jin Dan, Xu Bing, Dong Fuxing, Liu Zhiwei, Li Wei, Liu Hongmei, Qiao Yuehua
Department of Otorhinolaryngology-Head and Neck Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, P. R. China.
Artificial Auditory Laboratory of Jiangsu Province, Xuzhou Medical University, Xuzhou, 221002, P. R. China.
Adv Healthc Mater. 2025 Mar;14(7):e2403537. doi: 10.1002/adhm.202403537. Epub 2025 Jan 26.
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.
噪声性听力损失（NIHL）是由于长期暴露于高强度噪声导致感觉性外毛细胞（OHC）和螺旋神经节神经元（SGN）受损所致。血迷路屏障（BLB）阻碍了全身药物向内耳的递送。本研究采用耳后圆窗膜（RWM）方法绕过BLB，使大分子蛋白质能够转运至内耳。具有抗炎和神经保护特性的色素上皮衍生因子（PEDF）与靶向prestin的肽2（PrTP2）使用N-琥珀酰亚胺基-3-马来酰亚胺丙酸酯（SMP）偶联形成PrTP2-SMP/PEDF。该化合物特异性靶向prestin并在内毛细胞周围聚集以实现持续释放，有效减少内毛细胞和螺旋神经节神经元的损失。包括听性脑干反应（ABR）、共聚焦显微镜和扫描电子显微镜（SEM）在内的功能和结构测试显示听力有显著恢复和细胞保护作用。此外，酶联免疫吸附测定（ELISA）、膜联蛋白V和碘化丙啶（PI）染色以及免疫印迹结果表明，噪声暴露可能通过激活NOD样受体蛋白3（NLRP3）-含半胱天冬酶激活和招募结构域的凋亡相关斑点样蛋白（ASC）-半胱氨酸天冬氨酸特异性蛋白酶（Caspase-1）途径诱导耳蜗焦亡，而PrTP2-SMP/PEDF通过抑制焦亡减轻炎症反应。毒性分析表明无不良反应，提示PrTP2-SMP/PEDF对噪声性听力损失具有良好的治疗前景。
