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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 carrier-drug conjugate has the potential for applications in a variety of GPCR-mediated gastrointestinal diseases.<\/jats:p>","DOI":"10.1126\/scitranslmed.ado5177","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T18:59:24Z","timestamp":1763578764000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":8,"title":["Intestinal TGR5-targeted carrier-drug conjugate improves glycemic control in mice and pigs"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8385-9704","authenticated-orcid":true,"given":"Yaqi","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Drug Research and Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, 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