Ultra-small FePt/siRNA loaded mesoporous silica nanoplatform to deplete cysteine for enhanced ferroptosis in breast tumor therapy

The upregulation of redox systems inside malignant cells provides a powerful shelter against reactive oxygen species (ROS), hampering the antitumor response of ROS-based therapy. To address this issue, we report a strategy of cysteine depletion to block redox systems and enhance ferroptosis (a ROS-induced cell-death pathway) based on a mesoporous silica nanoplatform (sSFP) coloaded with FePt nanoparticles and siRNA. Through responding to high H2O2 in tumor microenvironment, the ferroptosis agent FePt triggered tumor cell ferroptosis via Fe2+-mediated Fenton reaction. In the meanwhile, siRNA released from sSFP interfered the over-expressed system xC– (the cystine/glutamate antiporter) subunit, xCT, in tumor cells and hindered cysteine intake, resulting the disturbance of redox systems including the glutathione redox system and the thioredoxin redox system. For the overexpressed xCT protein in tumor cells and tumor selectivity of Fenton reaction, this nanoplatform provides a high selectivity for destroying tumors. The subcutaneous xenograft model of breast tumor further verified the enhanced therapeutic effect.