Dual-modal antioxidant nanozyme hydrogel for protection against noise-induced hearing loss via attenuation of oxidative stress and NF-κB/MAPK signaling

Noise-induced hearing loss (NIHL) is a prevalent condition caused by irreversible cochlear hair cell damage resulting from an oxidative stress imbalance. To combat this, we engineered a yolk-shell shaped hollow Prussian blue nanozyme, loaded with N -acetylcysteine (NAC) and surface-modified with reactive oxygen species (ROS)-responsive liposomes, which was then incorporated into a tissue-adhesive hydrogel (HN@TK-Lipo gel ). This system establishes a dual-modal antioxidant mechanism, where the nanozyme acts as a continuous ROS scavenger and NAC replenish intrinsic antioxidant capacity. The hydrogel exhibits superior adhesiveness, effectively overcoming rapid drainage challenges in the middle ear. In vitro, HN@TK-Lipo gel demonstrated potent antioxidative capabilities, successfully scavenging intracellular ROS and preserving mitochondrial function. Crucially, in an NIHL animal model, the hydrogel treatment significantly alleviated auditory threshold shifts and minimized hair cell apoptosis and ribbon synapse loss. Transcriptomic analysis (RNA-seq) uncovered that the hydrogel exerts its protective effects by specifically downregulating inflammation-related pathways. Further mechanistic validation confirmed that HN@TK-Lipogel elicits an enhanced therapeutic effect by robustly upregulating antioxidant defenses (NRF2/SOD2) and suppressing lipid peroxidation (4-HNE) via the regulation of the identified NF-κB and MAPK signaling cascades. This biomaterial combines targeted delivery with enhanced catalytic and biological functions, improving the safety and effectiveness of inner ear therapy. Therefore, this nanozyme hydrogel system offers a promising therapeutic strategy for auditory medicine.