Selenium Nanodots (SENDs) as Antioxidants and Antioxidant-Prodrugs to Rescue Islet β Cells in Type 2 Diabetes Mellitus by Restoring Mitophagy and Alleviating Endoplasmic Reticulum Stress.

Abstract

Preventing islet β-cells death is crucial for treating type 2 diabetes mellitus (T2DM). Currently, clinical drugs are being developed to improve the quality of T2DM care and self-care, but drugs focused on reducing islets β-cell death are lacking. Given that β-cell death in T2DM is dominated ultimately by excessive reactive oxygen species (ROS), eliminating excessive ROS in β-cells is a highly promising therapeutic strategy. Nevertheless, no antioxidants have been approved for T2DM therapy because most of them cannot meet the long-term and stable elimination of ROS in β-cells without eliciting toxic side-effects. Here, it is proposed to restore the endogenous antioxidant capacity of β-cells to efficiently prevent β-cell death using selenium nanodots (SENDs), a prodrug of the antioxidant enzyme glutathione peroxidase 1 (GPX1). SENDs not only scavenge ROS effectively, but also "send" selenium precisely to β-cells with ROS response to greatly enhance the antioxidant capacity of β-cells by increasing GPX1 expression. Therefore, SENDs greatly rescue β-cells by restoring mitophagy and alleviating endoplasmic reticulumstress (ERS), and demonstrate much stronger efficacy than the first-line drug metformin for T2DM treatment. Overall, this strategy highlights the great clinical application prospects of SENDs, offering a paradigm for an antioxidant enzyme prodrug for T2DM treatment.