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.

Acute liver injury (ALI) is a severe liver disease that is characterized by sudden and massive hepatocyte necrosis and deterioration of liver functions. Oxidative stress is increasingly recognized as a key factor in the induction and progression of ALI. Scavenging excessive reactive oxygen species (ROS) with antioxidants has become a promising therapeutic option, but intrinsically hepatocyte‐targeting antioxidants with excellent bioavailability and biocompatibility are yet to be developed. Herein, self‐assembling nanoparticles (NPs) composed of amphiphilic polymers are introduced to encapsulate organic Selenium compound L‐Se‐methylselenocysteine (SeMC) and form SeMC NPs, which protect the viabilities and functions of cultured hepatocytes in drug‐ or chemical‐induced acute hepatotoxicity models via efficient ROS removal. After further functionalization with the hepatocyte‐targeting ligand glycyrrhetinic acid (GA), the resultant GA‐SeMC NPs exhibit enhanced hepatocyte uptake and liver accumulation. In mouse models of ALI induced by acetaminophen (APAP) or carbon tetrachloride (CCl₄), treatment with GA‐SeMC NPs significantly decrease the levels of hepatic lipid peroxidation, tissue vacuolization and serum liver transaminases, while prominently increase that of endogenous antioxidant enzymes. Our study therefore presents a liver‐targeting drug delivery strategy for the prevention and treatment of hepatic diseases.