ROS-Responsive Selenocysteine-Releasing Nanozyme for Targeted Ferroptosis Suppression and Pancreatic β-Cell Protection in Type 2 Diabetes

Abstract Pancreatic β-cell ferroptosis, driven by oxidative stress and impaired glutathione peroxidase 4 (GPX4) activity, has emerged as an important contributor to the progression of type 2 diabetes mellitus (T2DM). However, persistent reactive oxygen species (ROS) accumulation and insufficient selenocysteine (Sec) availability limit GPX4-dependent antioxidant defense, making effective ferroptosis intervention challenging. Here, we engineered a ROS-responsive Sec-loaded copper-based single-atom nanozyme (Se@CuSAzyme) that combines catalytic ROS scavenging with Sec supplementation. Benefiting from its intrinsic superoxide dismutase- and catalase-like activities, Se@CuSAzyme efficiently eliminated excessive ROS, while oxidative stress-triggered Sec release enhanced GPX4 expression. As a result, Se@CuSAzyme markedly suppressed high glucose and erastin-induced ferroptosis, reduced lipid peroxidation, and preserved mitochondrial integrity in pancreatic β-cells. In high-fat diet/streptozotocin-induced diabetic mice, Se@CuSAzyme demonstrated therapeutic efficacy comparable to that of metformin in ameliorating hyperglycemia, alleviating insulin resistance, and increasing energy expenditure. Importantly, Se@CuSAzyme outperformed metformin in protecting against hepatic steatosis and glycolipid metabolic dysfunction.