LAUSR

Abstract We have previously demonstrated that selenium nanoparticles (SeNPs) administered via oral route possess similar capacities of increasing selenoenzyme activities as the extensively examined sodium selenite, selenomethionine and methylselenocysteine, and yet display the lowest toxicity among these selenium compounds in mouse models. However, the low toxicity of SeNPs found in mammalian systems would lead to the interpretation that the punctate distribution of elemental selenium found in cultured cancer cells subjected to selenite treatment that triggers marked cytotoxicity represents a detoxifying mechanism. The present study found that SeNPs could be reduced by the thioredoxin‐ or glutaredoxin‐coupled glutathione system to generate ROS. Importantly, ROS production by SeNPs in these systems was more efficient than by selenite, which has been recognized as the most redox‐active selenium compound for ROS production. This is because multiple steps of reduction from selenite to selenide anion are required; whereas only a single step reduction from the elemental selenium atom to selenide anion is needed to trigger redox cycling with oxygen to produce ROS. We thus speculated that accumulation of SeNPs in cancer cells would result in a strong therapeutic effect, rather than serves a detoxification function. Indeed, we showed herein that preformed SeNPs generated a potent therapeutic effect in a mouse model due to rapid, massive and selective accumulation of SeNPs in cancer cells. Overall, for the first time, we demonstrate that SeNPs have a stronger pro‐oxidant property than selenite and hyper‐accumulation of SeNPs in cancer cells can generate potent therapeutic effects. Graphical abstract Figure. No caption available. HighlightsSeNPs hijack Trx‐ and Grx‐coupled GSH systems to generate ROS.ROS production by SeNPs in above systems is more efficient than by selenite.Intraperitoneal injection of SeNPs potently kills intraperitoneal cancer cells.Se in the cancer cells is rapidly hyper‐accumulated.Se in the cancer cells exists almost entirely as SeNPs.