Atomically dispersed copper(i) on tungstosilicic acid for catalytic protection against cisplatin-induced hearing loss

Abstract

The employment of platinum-based drugs for cancer chemotherapy, which might yield oxidative stress, is regarded as one main factor leading to hearing loss. The exact molecular mechanisms for cisplatin-induced hearing loss require further clarification, thus limiting the development of FDA-approved therapies. Herein, we mimicked the molecular structure of natural antioxidative enzymes to fabricate a four-oxygen-coordinating copper single-atom nanozyme (Cu SAN) exhibiting good superoxide dismutase and catalase activity, to alleviate the oxidative stress induced by platinum-based drugs. Notably, Cu SAN exhibited profound protective effects against cisplatin-induced hair cell damage with only 15 ng mL⁻¹ of Cu species, successfully reversing cisplatin-induced hearing loss via oral administration. Due to its oxidation resistance, pretreatment with Cu SAN significantly improved cell viability and reduced ROS accumulation in cisplatin-triggered hair cell damage in HEI-OC1 cells and cochlear explants. Our results first demonstrated that cisplatin treatment induced cuproptosis in hair cells by modulating copper ion homeostasis. Further investigation revealed that Cu SAN nanozyme effectively alleviated hair cell cuproptosis by regulating FDX1 and reducing aggregated lipoacylated protein. This research underscores the promising potential of four-oxygen-coordinating Cu nanomaterials as a therapeutic approach to combat hearing loss, providing a new strategy for auditory protection.