Semiconducting polymer nanoprodrugs enable tumor-specific therapy via sono-activatable ferroptosis

Ferroptosis, a recently identified form of cell death, holds promise for cancer therapy, but concerns persist regarding its uncontrolled actions and potential side effects. Here, we present a semiconducting polymer nanoprodrug (SPN_pro) featuring an innovative ferroptosis prodrug (DHU-CBA7) to induce sono-activatable ferroptosis for tumor-specific therapy. DHU-CBA7 prodrug incorporate methylene blue, ferrocene and urea bond, which can selectively and specifically respond to singlet oxygen (¹O₂) to turn on ferroptosis action via rapidly cleaving the urea bonds. DHU-CBA7 prodrug and a semiconducting polymer are self-assembled with an amphiphilic polymer to construct SPN_pro. Ultrasound irradiation of SPN_pro leads to the production of ¹O₂ via sonodynamic therapy (SDT) of the semiconducting polymer, and the generated ¹O₂ activated DHU-CBA7 prodrug to achieve sono-activatable ferroptosis. Consequently, SPN_pro combine SDT with the controlled ferroptosis to effectively cure 4T1 tumors covered by 2-cm tissue with a tumor inhibition efficacy as high as 100 %, and also completely restrain tumor metastases. This study introduces a novel sono-activatable prodrug strategy for regulating ferroptosis, allowing for precise cancer therapy.