Poly(amino acid) nanoprodrugs mitigate cisplatin-induced ototoxicity.

Cisplatin is a first-line chemotherapeutic agent for solid and metastatic tumors, yet its ototoxicity remains a major clinical challenge, causing irreversible, bilateral, dose-dependent sensorineural hearing loss. This toxicity severely impairs patients' quality of life and, in children, disrupts language and socio-cognitive development. Conventional strategies using antioxidants, anti-inflammatory agents, or molecular inhibitors only partially mitigate ototoxicity, while systemic administration compromises cisplatin's antitumor efficacy. Intratympanic delivery reduces systemic interference, but small-molecule drugs suffer from poor solubility, low stability, and short half-lives, necessitating frequent dosing that increases risks of local trauma and infection. Advanced biomaterial-based delivery systems provide promising solutions by protecting therapeutics, enhancing local bioavailability, and minimizing systemic toxicity. Poly(amino acid)s are attractive carriers due to their biocompatibility, biodegradability, and tunable side chains. Here, we developed amphiphilic poly(amino acid)s with intrinsic antioxidant activity and engineered nanoprodrugs via covalent conjugation with antioxidant drugs. Administered intratympanically, these self-assembled micelles exhibited prolonged cochlear retention. Mechanistically, the nanoprodrugs alleviated ototoxicity by reducing intracellular cisplatin accumulation through drug chelation and simultaneously scavenging cisplatin-induced reactive oxygen species within cells. This "dual-function" action significantly preserved hearing, providing both mechanistic insight and a potential therapeutic strategy for cisplatin-induced ototoxicity and other hearing impairments.