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.