Intracellular Redox Environment Determines Cancer‐normal Cell Selectivity of Selenium Nanoclusters

Abstract Elucidating the chemical structure and intracellular action mechanisms is still the critical limit for the clinical translation of nanomedicines. Intracellular redox environments originating from cell metabolism are key factors affecting internalized drug efficacy. Herein, we engineer Se−Se/Se−S bond to assemble selenium (Se) nanoclusters (SeClus) with intracellular redox environment‐driven selective structure. Chemical structure analysis reveals that, the bonding of sulfur atom in intermediates to the two neighboring or interposition Se atoms in Se rings is the key internal driving force for SeClus formation. This nanocluster can be predominantly transformed to selenocysteine to facilitate selenoproteins synthesis in normal cells, while metabolize to cytotoxic SeO 3 2− based on the oxidative intracellular redox environment of cancer cells. Resultantly, SeClus exhibit significant cell proliferation inhibition ability to cancer cells and impressive safety to normal cells. Taken together, this study not only clarifies the chemical nature of the atom engineering of SeClus, but also elucidates its intracellular redox environment‐oriented anticancer mechanism.