Intestinal TGR5-targeted carrier-drug conjugate improves glycemic control in mice and pigs

作者：Yaqi Zhang, Hui Huang, Yaying Wang, Xiang Li, Pan‐Yu Hou, Miaorong Yu, Zhuan Zhang, Shiyan Guo, Chang Liu, Zilong Zhang, Yan Zhuo, Chunliu Zhu, Pengcheng Zhang, Shisheng Wang, Hu Zhou, Yong Gan · 发表于：Science Translational Medicine · 年份：2025 · DOI：10.1126/scitranslmed.ado5177 · 被引用次数：5 · 研究领域：Diabetes Treatment and Management、Receptor Mechanisms and Signaling、Drug Transport and Resistance Mechanisms

Numerous G protein-coupled receptors (GPCRs) expressed in the gastrointestinal tract serve as crucial transducers to regulate a variety of physiological functions upon activation. Takeda G protein-coupled receptor 5 (TGR5), a prominent gastrointestinal GPCR expressed on enteroendocrine L cells, is activated by intestinal bile acids and plays a role in glucose utilization. However, the development of TGR5 agonists has been hindered by the hepatobiliary toxicity associated with long-term supplementation with exogenous agonists. Here, we designed and characterized a biomimetic receptor agonist, which we termed TGR5-targeted carrier-drug conjugate (TGR5-CaDC), that combined the TGR5-activating capabilities of deoxycholic acid, a TGR5 agonist, with the nonabsorbable properties of a carrier. Unlike traditional agonists or carrier-based drug delivery systems, nonabsorbable TGR5-CaDC remained localized in the intestines of mice and pigs, providing high surface concentrations of TGR5 agonists in addition to ensuring strong L cell specificity and TGR5 affinity. TGR5-CaDC treatment also promoted TGR5 cluster aggregation, signal amplification, and increased glucagon-like peptide 1 secretion. Notably, TGR5-CaDC demonstrated sustained glycemic effects with reduced toxicity compared with deoxycholic acid alone or liraglutide in diabetic mice and Bama minipigs. By targeting extracellular binding domains and mimicking native ligand-receptor binding patterns, the design concept underlying this...