Core Viewpoint - The article discusses a novel non-absorptive carrier-drug conjugate (CaDC) strategy targeting TGR5, which shows promise in improving glycemic control while minimizing liver toxicity associated with traditional TGR5 agonists [2][3][4]. Group 1: Research Findings - TGR5 is an important GPCR expressed in the gastrointestinal tract that, when activated, promotes GLP-1 secretion and plays a role in glucose utilization [2]. - The newly developed TGR5-targeted CaDC demonstrates superior glycemic control compared to the GLP-1 receptor agonist liraglutide, addressing the challenge of liver toxicity in TGR5 agonist development [3][7]. - The CaDC is designed to remain localized in the intestinal lumen, ensuring sustained activation of TGR5 without entering systemic circulation, thus enhancing safety [4][6]. Group 2: Mechanism and Efficacy - The TGR5-CaDC utilizes a biomimetic receptor agonist with a mesoporous silica particle framework, modified with deoxycholic acid as the TGR5 agonist, allowing for prolonged retention in the gut [4][6]. - In studies with diabetic mice and miniature pigs, TGR5-CaDC exhibited sustained blood sugar-lowering effects and lower toxicity compared to deoxycholic acid or liraglutide alone [7]. Group 3: Broader Implications - The design concept of CaDC, which targets the extracellular binding domain and mimics natural ligand-receptor interactions, has potential applications in various gastrointestinal diseases mediated by GPCRs [9].