Cell-membrane targeting sonodynamic therapy combination with FSP1 inhibition for ferroptosis-boosted immunotherapy

Cell membrane targeting sonodynamic therapy could induce the accumulation of lipid peroxidation (LPO), drive ferroptosis, and further enhances immunogenic cell death (ICD) effects. However, ferroptosis is restrained by the ferroptosis suppressor protein 1 (FSP1) at the plasma membrane, which can catalyze the regeneration of ubiquinone (CoQ10) by using NAD(P)H to suppress the LPO accumulation. This work describes the construction of US-active nanoparticles (TiF NPs), which combinate cell-membrane targeting sonosensitizer TBT-CQi with FSP1 inhibitor (iFSP1), facilitating cell-membrane targeting sonodynamic-triggered ferroptosis. TiF NPs could induce a sonodynamic effect, which promotes lipid peroxidation and drives apoptosis. Furthermore, TiF NPs could suppress FSP1, induce CoQ10 depletion, down-regulate the NADH, enhance LPO accumulation, and finally induce ferroptosis. In vitro results demonstrated that synergetic cell membrane targeting SDT/FSP1 inhibition triggered immunogenic cell death (ICD). Moreover, the as-synthesized TiF NPs-mediated cell membrane targeting SDT/FSP1 inhibition thoroughly inhibited the tumor growth and simultaneously activated antitumor immunity to suppress lung metastasis. This work represents a promising tumor therapeutic strategy combining cell membrane targeting SDT and FSP1 inhibition, potentially inspiring further research in developing logical and effective cancer therapies based on synergistic SDT/ferroptosis. [Display omitted] •TBT-CQi could accumulate in the cell membrane and generate ROS in situ under US irradiation.•TBT-CQi and FSP1 inhibitor (iFSP1) were encapsulated in DSPE-PEG2000 to afford TiF NPs, which could drive apoptosis.•TiF NPs could suppress FSP1, deplete CoQ10, down-regulate NADH, enhance LPO accumulation, and trigger ferroptosis.•TiF NPs could activate ICD effect and trigger systemic antitumor immunity for tumor regression and metastasis suppression.