An Organelle‐Specific Nanozyme for Diabetes Care in Genetically or Diet‐Induced Models

Abstract The development of nanozymes has made active impact in diagnosis and therapeutics. However, understanding of the full effects of these nanozymes on biochemical pathways and metabolic homeostasis remains elusive. Here, it is found that iron oxide nanoparticles (Fe₃O₄ NPs), a type of well‐established nanozyme, can locally regulate the energy sensor adenosine 5′‐monophosphate‐activated protein kinase (AMPK) via their peroxidase‐like activity in the acidic lysosomal compartment, thereby promoting glucose metabolism and insulin response. Fe₃O₄ NPs induce AMPK activation and enhance glucose uptake in a variety of metabolically active cells as well as in insulin resistant cell models. Dietary Fe₃O₄ NPs display therapeutic effects on hyperglycemia and hyperinsulinemia in Drosophila models of diabetes induced by genetic manipulation or high‐sugar diet. More importantly, intraperitoneal administration of Fe₃O₄ NPs stimulates AMPK activities in metabolic tissues, reduces blood glucose levels, and improves glucose tolerance and insulin sensitivity in diabetic ob/ob mice. The study reveals intrinsic organelle‐specific properties of Fe₃O₄ NPs in AMPK activation, glycemic control, and insulin‐resistance improvement, suggesting their potential efficacy in diabetes care.