Targeted inhibition of hepatic phosphoinositide 3-kinase
in: Science Translational Medicine (2020)
Jaundice is a late feature of sepsis-related hepatic dysfunction and is associated with poor outcomes. Phosphoinositide 3-kinases (PI3K) mediate critical functions within multiple cells, including phase I, II, and III metabolism by the liver and immune defense mechanisms. Mice lacking PI3Kγ are protected against hepatic excretory dysfunction yet exhibit a severe immune defect that impairs neutrophil recruitment to sites of infection. To exploit the therapeutic potential of PI3Kγ inhibition, a targeted delivery strategy is needed whereby specific tissues are selected yet without compromising others such as immune functionality. Here we demonstrate that nanocarriers functionalized through fluorescent ligands of organic anion transporters are suitable for delivery of therapeutics selectively to liver parenchyma. Applying this strategy to a murine model of sepsis, we observed PI3Kγ-dependent restoration of biliary canalicular architecture through modulation of RhoA. This approach maintained excretory liver function and improved survival without impairing host defense mechanisms.