Intrahepatic cholestasis in pregnancy (ICP) is a characteristic disease during the perinatal period; however, its therapy remains unsatisfactory, and the pathogenesis remains unclear. The ameliorative effect of naturally occurring quercetin 7-rhamnoside (Q7R) in cholestasis has been established. In this study, we aimed to establish a nanoparticle-based peptide, A20FMDV2-modified liposome (t-QL), to encapsulate and deliver Q7R. Q7R bioavailability improved significantly when liposomes were used as carriers. This peptide A20FMDV2-modified nanosystem targeted integrin αvβ6 on biliary epithelial cells and improved stillbirth rates and liver function indicators better than free Q7R without a carrier. Q7R improved ICP by regulating mitochondrial function and bile metabolism. Our nanosystem provides a promising nanotherapeutic strategy for applying Q7R in ICP. We also elucidated a therapeutic mechanism underlying the action of ICP by simultaneously targeting mitochondrial structure and function, as well as bile acid metabolism.