A multifunctional nanocatalytic ferroptosis amplifier based on glutathione scavenging and lipid peroxidation amplification for cancer therapy.

Ferroptosis is a form of cell death characterized by decreased glutathione peroxidase 4 (GPX4) activity and amplification of lipid peroxidation cascades, efficiently disrupting cellular redox homeostasis. Photothermal therapy effectively regulates System Xc-, leading to the downregulation of GPX4, which plays a crucial role in promoting ferroptosis. However, the cellular self-protection mechanism of thermotolerance subsequently becomes a negative factor. Sonodynamic therapy (SDT) accumulates singlet oxygen (1O2), which facilitates the maintenance of reactive oxygen species and effectively alleviates thermotolerance during thermal elevation, while creating conditions for lipid peroxidation. This study constructed a nanodrug IrOx@HMME-HSA, in which the iridium oxide (IrOx) component guides photothermal effects and regulates the System Xc--glutathione (GSH)-GPX4 route, and hematoporphyrin monomethyl ether (HMME) enables SDT to generate ROS and lipid peroxides and eliminate heat resistance. This provides a novel strategy to address the self-hypoxic characteristics of tumor microenvironments, antioxidant defenses, and laser-responsive heat tolerance issues. In addition, it lays theoretical and experimental foundations for the application of iridium-based nano-drugs in cancer therapy enhanced by ferroptosis through amplified GSH depletion.