Redox-regulated in situ-forming hydrogel informed by single-cell transcriptomics for functional restoration of injured vocal folds

Vocal fold (VF) injury, frequently caused by laryngeal microsurgery, leads to fibrosis and phonation impairment. Effective therapies remain limited, partly due to limited understanding of VF injury mechanisms. Using single-cell RNA sequencing of injured human VFs, we identified marked oxidative stress upregulation in epithelial cells, highlighting the need for epithelial protection and redox modulation. Informed by this insight, we developed an in situ-forming redox-regulated hydrogel, compatible with endoscopic spray delivery. It forms a conformal gel on the VF surface within 2 seconds, providing physical shielding and oxidative microenvironment regulation. The hydrogel reduced intracellular and mitochondrial reactive oxygen species, activated endogenous protective mechanisms, preserved mitochondrial function, and consequently rescued epithelial cells from oxidative stress-induced apoptosis and proliferation loss. In vivo, the hydrogel accelerated epithelialization and restored functions (vibratory and phonatory). Overall, this study introduces a unique approach for functional VF repair and offers a promising paradigm for biomaterial development guided by pathological microenvironment. Vocal fold injury leads to fibrosis. Here, the authors identify oxidative stress as a key injury mechanism via single-cell sequencing and develop an in situ-forming hydrogel that provides physical shielding and redox regulation, restoring vibratory function.