细胞启发的双串联催化纳米反应器驱动靶向听力保护

文献信息

中文摘要

背景： 感音神经性听力损失由耳蜗稳态破坏驱动，其中氧化还原、离子和代谢因素失调导致毛细胞变性和突触损伤。当前策略缺乏恢复活性氧酶促清除或穿透血-迷路屏障的能力。方法：在此，我们报道了一种细胞启发的双串联催化纳米反应器（HSC@Se），将GPx模拟的二硒化物与超氧化物歧化酶和过氧化氢酶整合，以重建解毒级联反应。我们表明，白蛋白支架稳定了纳米结构，并通过中性粒细胞黏附转运和megalin介导的摄取实现主动穿透血-迷路屏障，促进向毛细胞和螺旋神经节神经元的耳蜗递送。结果：在噪声诱导的小鼠模型中，我们证明HSC@Se恢复氧化还原平衡、抑制铁死亡、正常化铁处理、保持毛细胞完整性、维持带状突触并减少听阈偏移。我们进行转录组学以揭示抗氧化和代谢修复通路的激活。结论：这项工作提出了细胞启发的纳米反应器，其模拟天然抗氧化网络以重新平衡耳蜗氧化还原稳态并驱动听力保护。

英文摘要

Sensorineural hearing loss is driven by disruption of cochlear homeostasis, where dysregulated redox, ionic, and metabolic factors lead to hair cell degeneration and synaptic injury. Current strategies lack the capacity to restore the enzymatic clearance of reactive oxygen species or penetrate the blood-labyrinth barrier. Here, we report a cell-inspired dual-tandem catalytic nanoreactor (HSC@Se) integrating GPx-mimetic diselenide with superoxide dismutase and catalase to reconstruct the detoxification cascade. We show that the albumin scaffold stabilizes the nanoarchitecture and enables active blood-labyrinth barrier penetration of neutrophil-adhesive transport and megalin-mediated uptake, facilitating cochlear delivery to hair cells and spiral ganglion neurons. In noise-induced mouse models, we demonstrate that HSC@Se restores redox equilibrium, suppresses ferroptosis, normalizes iron handling, preserves hair-cell integrity, maintains ribbon synapses, and reduces auditory threshold shifts. We perform transcriptomics to reveal activation of antioxidative and metabolic repair pathways. This work presents cell-inspired nanoreactors that emulate natural antioxidant networks to rebalance cochlear redox homeostasis and drive hearing protection.