Since cholic acid receptors are rich on the membrane of intestine epithelial cells and hepatocytes, cholic acid was conjugated to DSPE–PEG, and functional nanoliposomes loaded with model drug silybin (CA–LPs–silybin) were constructed and characterized for oral administration and to target the liver. CA–LPs–silybin was found stable in terms of nanoliposome integrity after cellular transport via TEM imaging and HPLC analysis of the % of encapsulated silybin. The investigation of CA–LPs–silybin includes its transport and mechanisms across the ASBT-positive Caco-2 cell monolayers, its hepatic targeting efficiency and mechanisms via in vitro cell uptake studies in the NTCP-positive HepG2 cells and in vivo hepatic distribution. The results of the investigation showed that CA–LPs–silybin exhibited increased levels of intracellular transport and uptake in vitro and liver accumulation in vivo as compared with unmodified nanoliposomes, via a cholic acid receptor mediated mechanism. Inhibitor competition experiments suggest that CA–LPs–silybin is transported across Caco-2 cell monolayers through a transcellular but not a paracellular pathway and enters HepG2 cells through an unspecific endocytosis pathway and a specific lipid raft and clathrin-mediated mechanism.