Glutathione-scavenging ferroptotic nanoamplifiers strengthen tumour therapy through sonodynamic/photothermal-triggered GPX4 inhibition and lipid peroxidation

• In this study, we achieved bimetallic synergy to overcome ferroptosis resistance during therapy, which is primarily caused by intracellular regulatory abnormalities, such as enhanced glutathione biosynthesis. • Sonodynamic therapy is introduced to mediate reactive oxygen species generation, which not only reduces tumour thermoresistance but also significantly enhances the therapeutic efficacy of photothermal therapy. • It provides preclinical evidence for the utility of iridium-based nanomaterials in inducing ferroptotic cell death, expanding the toolbox of nanotherapeutics for refractory prostate cancer. Ferroptosis-based therapeutic strategies hold promise for overcoming the limitations of conventional therapies in modulating cell-death pathways, offering novel avenues for treating tumours that exhibit poor responsiveness to standard approaches. However, intrinsic regulatory mechanisms in tumour cells induce therapeutic resistance, severely impeding the antitumour efficacy of ferroptosis-inducing therapies. In this study, IrO x @TCPP-Cu nanomaterials were developed to enable dual-metal catalytic reduction of GSH and to mediate ferroptosis through sonodynamic and photothermal therapy (SDT/PTT) for the treatment of prostate cancer.The underlying mechanism is as follows: IrO x decomposes to generate oxygen, which enhances the sonodynamic activity of TCPP-Cu and promotes continuous production of singlet oxygen ( 1 O 2 ), leading to the accumulation of lipid peroxides (LPO)..Concurrently, IrO x -mediated PTT inhibits the System-Xc − pathway, leading to reduced expression of glutathione peroxidase 4 (GPX4). Furthermore, the redox cycling between Ir 4+ /Ir 3+ and Cu 2+ /Cu + depletes the intracellular GSH, thereby suppressing GPX4 activity. The burst of reactive oxygen species (ROS) induced by SDT overcomes the PTT-associated thermal resistance, thus enhancing the overall therapeutic efficacy. This cascaded effect disrupts ROS-GPX4 homeostasis, resulting in irreversible LPO accumulation and ultimately triggering ferroptotic cell death. Collectively, the Ir-based nanoclusters developed in this study represent a highly promising strategy for cancer ferroptosis therapy.