Intestinal TGR5-Targeted Carrier–Drug Conjugate Improves Glycemic Control in Mice and Pigs

Yong Gan – Professor, Shanghai Institute of Materia Medica, Chinese Academy of Sciences; Shiyan Guo – Senior Engineer, Shanghai Institute of Materia Medica, Chinese Academy of Sciences; Di Nie – Associate Research Fellow, Shanghai Institute of Materia Medica, Chinese Academy of Sciences; Miaorong Yu – Professor, Shanghai Institute of Materia Medica, Chinese Academy of Sciences; Chunliu Zhu – Senior Engineer, Shanghai Institute of Materia Medica, Chinese Academy of Sciences

Introduction:

Oral activation of intestinal TGR5 is a promising strategy to enhance endogenous GLP-1, yet small-molecule agonists often suffer from systemic absorption and off-target effects. We designed a gut-restricted, nonabsorbable carrier-drug conjugate that orally delivers high-density bile-acid agonists to the intestinal lumen and enables localized, multivalent stimulation of TGR5 on enteroendocrine L cells. This oral delivery approach aims to sustain GLP-1 secretion and improve glycemic control while minimizing systemic exposure and toxicity.