Manganese‐Based Redox Homeostasis Disruptor for Inducing Intense Ferroptosis/Apoptosis Through xCT Inhibition And Oxidative Stress Injury

Intracellular redox homeostasis plays an important role in promoting tumor progression, development and even treatment resistance. To this end, redox balance impairment may become a prospective therapeutic target of cancer. Herein, a manganese-based homeostasis modulator (MHS) is developed for inducing severe reactive oxygen species accumulation and glutathione (GSH) deprivation, where such redox dyshomeostasis brings about dramatic ferroptosis/apoptosis. Tumor-specific degradation of manganese oxide nanocarriers contributes to hypoxia alleviation and loaded cargo release, resulting in apoptosis by augmented sonodynamic therapy and chemodynamic therapy. On the other hand, regional oxygenation significantly downregulates the expression of activating transcription factor 4, which can synergize with the released sulfasalazine to inhibit the downstream cystine antiporter xCT. Biosynthesis of GSH is sufficiently interrupted by the xCT suppression, leading to the reduction of glutathione peroxidase 4 (GPx4) level. The resultant excessive lipid peroxides promote intense ferroptosis to motivate cell death. On this basis, splendid treatment outcome by MHS is substantiated both in vitro and in vivo, thanks to the synergy of antitumor immunity elicitation. Taken together, this paradigm provides an insightful strategy to evoke drastic ferroptosis/apoptosis toward therapeutics and may also expand the eligibility of manganese-derived nanoagents for medical applications.