Thioether-functionalized polycarbonate nanosponges mitigate cisplatin-induced ototoxicity via ROS scavenging and cisplatin deactivation

Cisplatin remains a first-line chemotherapeutic for a wide spectrum of solid and metastatic tumors; however, its dose-limiting ototoxicity severely compromises patients' quality of life and causes irreversible deficits in language development and socio-cognitive function in children. To address this challenge, we developed a multifunctional amphiphilic polycarbonate-based nanosponge platform (NPs@AST) loaded with astaxanthin, designed to mitigate cisplatin-induced ototoxicity. This system is synthesized through one-step ring-opening polymerization of a trithioether-containing bicyclic carbonate monomer, resulting in a core-crosslinked nanosponge with densely distributed thioether groups. These groups confer intrinsic ROS scavenging, ROS-triggered drug release, and cisplatin-chelating detoxification in a single, chemically defined platform. Upon transtympanic administration, NPs@AST exhibits prolonged cochlear retention and robust otoprotection via two synergistic mechanisms: (i) thioether groups chelate cisplatin, deactivating it and reducing intracellular accumulation; and (ii) intracellular ROS scavenging, coupled with ROS-triggered astaxanthin release, enhancing antioxidant defense against oxidative stress. In C57BL/6 mice, NPs@AST preserved auditory thresholds at ~35 dB on day 21, compared to ~70 dB in untreated controls, as assessed by auditory brainstem response. Therefore, this ROS-responsive polycarbonate nanoplatform offers a promising strategy to mitigate cisplatin-induced ototoxicity and lays the foundation for developing effective, low-toxicity inner-ear drug delivery systems.