Ferroptosis boosting system based on a sonodynamic therapy cascade-augmented strategy for triple-negative breast cancer therapy

Abstract One of the novel forms of programmed cell death, ferroptosis, has recently emerged as a hopeful treatment strategy for triple-negative breast cancer (TNBC). However, insufficient levels of intracellular reactive oxygen species (ROS) and high levels of ROS scavengers in the tumor microenvironment (TME), such as glutathione (GSH), hamper the efficacy of ferroptosis therapy. In this study, the introduction of manganese dioxide nanoparticles (MnO2 NPs) generated cytotoxic hydroxyl radicals (⋅OH) in the TME. Importantly, MnO2 NPs act as a nanosensitizer by consuming H2O2/GSH in the TME, generating oxygen (O2) to relieve the oxygen deficiency of tumors, induce tumor oxidative stress and ultimately enhance SDT-induced ferroptosis. Additionally, oxygen, as an ultrasound contrast agent, enables the visualization of the TNBC treatment process. Meanwhile, GSH depletion in the TME leads to failure of the major cellular system defending against ferroptosis, which also promotes the accumulation of lipid peroxidation in tumor tissue. Specifically, robust autophagy induced by ROS enhances the intracellular iron pool by breaking down ferritin, thereby promoting ferroptosis in cancer cells, leading to the optimal antitumor effect. Consequently, a ferroptosis boosting system that simultaneously encapsulates MnO2 NPs and chlorin e6 (Ce6) was constructed for the intervention of TNBC. Both the in vitro and in vivo results demonstrated that Ce6-MnO2-BSA nanoparticles can generate a significant ROS storm under ultrasound irradiation, eliminating GSH and inducing an autophagic response that increases the effectiveness of ferroptosis, thus, inhibiting the growth of TNBC without obvious toxic side effects. This effective strategy can cascade-augment cancer cell ferroptosis, providing a new perspective for the clinical treatment of TNBC.