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•Dendritic mesoporous SiO2 NPs were designed as a robust nano-support for metal NPs growth and RNA adsorption.•xCT silencing enabled cysteine depletion and hampered both GSH redox system and the TXN redox system.•Disturbance of the compensation mechanism between different redox systems magnified tumor ferroptosis.
A nanoplatform that integrates ferroptosis agent FePt nanoparticles and siRNA against system Xc- into dendritic mesoporous SiO2 was reported to deplete cysteine for enhanced ferroptosis in breast tumor therapy. [Display omitted]
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.