Galactosylated LNP-mediated hepatic Sam68 silencing improves glucose homeostasis in diabetes by suppressing gluconeogenesis

Excessive hepatic glucose production is a key driver of the progression of type 2 diabetes (T2DM), a highly prevalent global metabolic disorder. We previously reported that Sam68 expression is upregulated in the livers of both diabetic patients and mouse models, and hepatocyte-specific knockdown of Sam68 greatly alleviates hyperglycemia and improves insulin sensitivity in diabetic mice. Here, we engineered a series of ligand-functionalized lipid nanoparticles (LNPs) and identified a galactose-decorated formulation (LNP-Gal) that enables efficient hepatocyte-selective delivery of Sam68 siRNA, thereby achieving robust Sam68 silencing and suppressing hepatic gluconeogenesis in both cellular and animal models. In both genetic and diet-induced diabetic mouse models, systemic administration of siSam68/LNP-Gal improved glycemic control and insulin responsiveness and attenuated hepatic gluconeogenic output, accompanied by suppression of the hepatic gluconeogenic program. Thus, we establish siSam68/LNP-Gal as a hepatocyte-selective siRNA delivery system that elicits a potent antihyperglycemic effect with a favorable safety profile in vitro and in vivo, providing a promising siRNA-based strategy for the treatment of T2DM and related metabolic disorders.