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<p>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 <i>in vitro</i> and <i>in vivo</i>, providing a promising siRNA-based strategy for the treatment of T2DM and related metabolic disorders.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月14日

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  • Ning Wang,
  • Xiang Cao,
  • Jing Lai,
  • Yifan Gao,
  • Ao Yu,
  • Siyu An,
  • Yucheng Gao,
  • Ebenezeri Erasto Ngowi,
  • Juan Yang,
  • Chang Fu,
  • Junyu Xu,
  • Li Tian,
  • Haozhe Piao,
  • Shiyang Shen,
  • Aijun Qiao

摘要

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.

Graphical Abstract