Application of self-assembly palladium single-atom nanozyme over polyoxometalates in protection against neomycin-induced hearing loss by inhibiting ferroptosis

Deafness mainly results from irreversible impairment of hair cells (HCs), which may relate to oxidative stress, yet therapeutical solutions is lacked due to limited understanding on the exact molecular mechanism. Herein, mimicking the molecular structure of natural enzymes, a palladium (Pd) single-atom nanozyme (SAN) was fabricated, exhibiting superoxide dismutase and catalase activity, transforming reactive oxygen species (ROS) into O₂ and H₂O. We examined the involvement of Pd in neomycin-induced HCs loss in vitro and in vivo over zebrafish. Our results revealed that neomycin treatment induced apoptosis in HCs, resulting in substantial of ROS elevation in HEI-OC1 cells, decrease in mitochondrial membrane potential, and increase in lipid peroxidation and iron accumulation, ultimately leading to iron-mediated cell death. Noteworthy, Pd SAN treatment exhibited significant protective effects against HCs damage and impaired HCs function in zebrafish by inhibiting ferroptosis. Furthermore, the application of iron death inducer RSL3 resulted in notable exacerbation of neomycin-induced harm, which was mitigated by Pd administration. Our investigation demonstrates that antioxidants is promising for inhibiting ferroptosis and repairing of mitochondrial function in HCs and the enzyme-mimic SAN provides a good strategy for designing drugs alleviating neomycin-induced ototoxicity.