Single-Atom Ce-N₄-C-(OH)₂ Nanozyme-Catalyzed Cascade Reaction to Alleviate Hyperglycemia

The enzyme-mimicking catalytic activity of single-atom nanozymes has been widely used in tumor treatment. However, research on alleviating metabolic diseases, such as hyperglycemia, has not been reported. Herein, we found that the single-atom Ce-N₄-C-(OH)₂ (SACe-N₄-C-(OH)₂) nanozyme promoted glucose absorption in lysosomes, resulting in increased reactive oxygen species production in HepG2 cells. Furthermore, the SACe-N₄-C-(OH)₂ nanozyme initiated a cascade reaction involving superoxide dismutase-, oxidase-, catalase-, and peroxidase-like activity to overcome the limitations associated with the substrate and produce •OH, thus improving glucose intolerance and insulin resistance by increasing the phosphorylation of protein kinase B and glycogen synthase kinase 3β, and the expression of glycogen synthase, promoting glycogen synthesis to improve glucose intolerance and insulin resistance in high-fat diet-induced hyperglycemic mice. Altogether, these results demonstrated that the novel nanozyme SACe-N₄-C-(OH)₂ alleviated the effects of hyperglycemia without evident toxicity, demonstrating its excellent clinical application potential.