Self‐Amplifying Redox Dyshomeostasis: An All‐Active Fenton/Diselenium‐Based Nanocomposite for Multimechanistic Cancer Therapy

ABSTRACT Anticancer strategies based on redox modulation, including the induction of reactive oxygen species (ROS) generation and the depletion of the antioxidant glutathione (GSH), have shown significant efficacy toward precision tumor suppression. However, the clinical translation of Fenton catalysts focused on Fe 2+ is limited by insufficient endogenous tumor substrate H 2 O 2 and high dose requirements for ROS inducers. In addition, the dose‐dependent constraint between the efficacy and toxicity of some GSH‐depleting agents remains to be resolved. In order to efficiently disrupt the tumor redox homeostasis, an all‐active Fe‐Se synergistic nanocomposite system (denoted NSe‐GFe) is designed in this study by combining the block polycarbonate mPEG‐ b ‐P(M SeSe ‐ co ‐TMC) (PSe) and the Fenton catalyst GA‐Fe (II) (denoted GFe) via thin‐film hydration. NSe‐GFe can simultaneously affect redox levels through the production of toxic •OH and the substantial depletion of GSH. The “seesaw strategy” compensates for the limited efficacy of GFe due to insufficient H 2 O 2, as well as the side‐effects associated with NSe (nanomicelles formed by PSe) as a GSH‐depleting agent. NSe‐GFe induces ferroptosis and apoptosis in Hep3b cells and inhibits tumor angiogenesis by downregulating the expression of vascular endothelial growth factor A (VEGFA), thus ensuring both biosafety and tumor suppression in vivo. The efficacy of multiple pathways gives this composite nanoparticle potential in the treatment of cancer.