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