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) 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 (O) 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. Ultrasound irradiation of SPN leads to the production of O via sonodynamic therapy (SDT) of the semiconducting polymer, and the generated O activated DHU-CBA7 prodrug to achieve sono-activatable ferroptosis. Consequently, SPN 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.