In this contribution we summarize our observations over a period of nearly
two decennia on the role of hepatocytes in the hepatic clearance of intrave
nously administered liposomes. We demonstrate that, although size is an imp
ortant parameter, it is not decisive in determining access of liposomes to
the hepatocytes. Also lipid composition is an important parameter, includin
g charge, rigidity and headgroup composition. The role of the fenestrated s
inusoidal endothelial cells in accessibility is discussed as well as the in
volvement of opsonizing plasma proteins such as apolipoprotein E. Our obser
vations led us to hypothesize at least four different mechanisms of interac
tion of liposomes with hepatocytes.