High‐Valence Selenium Nanotherapeutics Downregulates MUC16 to Drive Precise Ovarian Cancer Therapy through Redox Perturbation

Abstract Abnormal expression of transmembrane mucin 16 (MUC16) in ovarian cancer (OC) can promote progression of epithelial–mesenchymal transformation, enhance tumor cell proliferation, migration, and invasion. Therefore, herein a targeted therapeutic high‐valence selenium (Se) nanomedicine (MUC16‐SeMnf@Res) is designed, which can target MUC16 to recognize OC and simultaneously inhibit MUC16 expression to achieve efficient treatment of OC. The valence bidirectional editing strategy is used to design and synthesize a high‐valence Se nanosystem (SeMnf) through triggering a redox reaction between triclinic Se and manganese dioxide nanoflower (Mnf), and inducing the valence conversion to Se 4+ and Mn 2+ . The high‐valence Se 4+ and increased Mn 2+ ratio within SeMnf disrupt intracellular redox homeostasis by inducing glutathione (GSH) depletion and reactive oxygen species (ROS) overproduction. Moreover, the effects of ROS overproduction are further amplified by loaded resveratrol (Res), which significantly induces mitochondrial dysfunction and inhibited MUC16 expression, then promoting caspase‐activated cell apoptosis as well as migration inhibitory. Taken together, this study not only sheds light on the important role of MUC16 in designing OC‐targeting drugs, but also provides a simple and translational strategy by developing Se nanotherapeutics with strong redox‐homeostasis disrupting capability to realize MUC16‐targeting therapy.