Xu Ke, Li Wenjing, Jiang Qingjun, Yu Dehong, Chen Yu, Wang Xueling
Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai 200011, China; Biobank of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Materdicine Lab, School of Life Sciences, Shanghai University, Shanghai 200444, China.
J Control Release. 2025 Sep 10;385:114006. doi: 10.1016/j.jconrel.2025.114006. Epub 2025 Jul 7.
The treatment of noise-induced hearing loss (NIHL) is challenged by the blood-labyrinth barrier (BLB), which impedes effective drug delivery to the cochlea. NIHL serves as a model for sensorineural hearing loss (SNHL), highlighting the urgent need for advanced therapeutic strategies that can traverse BLB and target cochlear pathology. Here, we report the development of tFNA-RA@G-Ang2, a multi-stage, biomimetic nanocomposite designed for targeted inner ear therapy. This platform integrates tetrahedral framework nucleic acids (tFNA) to enhance cellular internalization, gelatin nanoparticles (GNPs) with MMP2-responsive degradability for dynamic size modulation, and Ang2 peptide functionalization for low-density lipoprotein receptor-related protein 1 (LRP1)-mediated transcytosis across the BLB. These features enable efficient delivery of rosmarinic acid (RA) to cochlear synapses and neurons, maximizing neuroprotection and antioxidant effects. The enzymatic degradation of GNPs enables controlled nanoparticle disassembly, facilitating deep cochlear penetration and prolonged retention. In vitro and in vivo studies demonstrate that tFNA-RA@G-Ang2 significantly reduces oxidative stress, protects cochlear ribbon synapses, prevents neuronal apoptosis, and restores auditory function in NIHL treatment. This approach outperforms conventional delivery systems by integrating biomimetic targeting, enzymatic-triggered adaptability, and spatiotemporal control. Collectively, our work offers a versatile platform for overcoming BLB-related therapeutic barriers, with broad implications for NIHL, age-related hearing loss, ototoxicity, and inner ear neuroprotection.
血迷路屏障（BLB）阻碍了药物有效递送至耳蜗，这给噪声性听力损失（NIHL）的治疗带来了挑战。NIHL是感音神经性听力损失（SNHL）的一个模型，凸显了对能够穿越BLB并靶向耳蜗病变的先进治疗策略的迫切需求。在此，我们报告了tFNA-RA@G-Ang2的研发情况，这是一种为靶向内耳治疗而设计的多阶段仿生纳米复合材料。该平台整合了四面体框架核酸（tFNA）以增强细胞内化，具有基质金属蛋白酶2（MMP2）响应性降解能力以实现动态尺寸调节的明胶纳米颗粒（GNP），以及用于低密度脂蛋白受体相关蛋白1（LRP1）介导的跨BLB转胞吞作用的血管生成素2（Ang2）肽功能化。这些特性能够将迷迭香酸（RA）高效递送至耳蜗突触和神经元，最大化神经保护和抗氧化作用。GNP的酶促降解能够实现纳米颗粒的可控拆解，促进其深入耳蜗并延长滞留时间。体外和体内研究表明，tFNA-RA@G-Ang2在NIHL治疗中可显著降低氧化应激、保护耳蜗带状突触、防止神经元凋亡并恢复听觉功能。这种方法通过整合仿生靶向、酶触发适应性和时空控制，优于传统递送系统。总体而言，我们的工作提供了一个克服与BLB相关治疗障碍的通用平台，对NIHL、年龄相关性听力损失、耳毒性和内耳神经保护具有广泛意义。
