Nanomodulation of blood-labyrinth barrier enhances neuroprotection and antioxidant intervention for noise-induced hearing loss.

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.