Prevention of hair cell death is an important target for the prevention of hearing loss. Here, we report the engineering of biodegradable poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) decorated with triphenylphosphonium (TPP) cations as a robust mitochondrial delivery platform, with the aim of preserving mitochondrial integrity and shutting off the initiation of cell death. Geranylgeranylacetone (GGA), a 70 kDa heat shock protein (HSP70) inducer, was used as a therapeutic molecule to attenuate gentamicin (Gen) induced hearing loss. The diameter of the mitochondria-targeting NPs is 145 nm and the encapsulation efficiency is 80.6%. Lysosomal escape and mitochondrial targeting studies indicated the promising therapeutic potential of TPP modified NPs. Finally, the zebrafish lateral line model was applied to verify the efficacy of the GGA loaded targeting NPs for preventing gentamicin-induced death hair cell. The results showed that the prepared targeted NPs provided significant protection: the survival of hair cells increased from 36% to 69% under acute exposure and from 20% to 62% under chronic exposure. In addition, targeted NPs exhibited significantly improved efficiency in alleviating gentamicin-induced hair cell damage compared with free drugs and untargeted NPs, supporting the hypothesis of mitochondrial targeting delivery in the treatment of aminoglycoside-induced hearing loss. These TPP modified NPs demonstrated promise for the treatment of mitochondrial dysfunction.

中文翻译：

---

三苯基phosph修饰的纳米粒子靶向将香叶基香叶基丙酮递送至线粒体：防止氨基糖苷类引起的听力损失的有前途的策略†

预防毛细胞死亡是预防听力损失的重要目标。在这里，我们报告的可生物降解的聚工程（乳酸-共-乙醇酸）纳米粒子（PLGA NPs）修饰了三苯基（（TPP）阳离子作为强大的线粒体递送平台，目的是保持线粒体的完整性并阻止细胞死亡的开始。70 kDa热休克蛋白（HSP70）诱导剂Geranylgeranylacetone（GGA）被用作减轻庆大霉素（Gen）引起的听力损失的治疗分子。靶向线粒体的NP的直径为145 nm，封装效率为80.6％。溶酶体逃逸和线粒体靶向研究表明，TPP修饰的NP具有广阔的治疗潜力。最后，斑马鱼侧线模型用于验证GGA负载的靶向NPs预防庆大霉素诱导的死亡毛细胞的功效。结果表明，制备的靶向NP提供了显着的保护：在急性暴露条件下，毛细胞的存活率从36％增加到69％，在慢性暴露条件下则从20％增加到62％。此外，与游离药物和非靶向NP相比，靶向NP在缓解庆大霉素诱导的毛细胞损伤方面显示出显着提高的效率，支持线粒体靶向递送治疗氨基糖苷诱导的听力损失的假说。这些TPP修饰的NPs有望用于治疗线粒体功能障碍。支持线粒体靶向递送治疗氨基糖苷类引起的听力损失的假说。这些TPP修饰的NPs有望用于治疗线粒体功能障碍。支持线粒体靶向递送治疗氨基糖苷类引起的听力损失的假说。这些TPP修饰的NPs有望用于治疗线粒体功能障碍。