Therapeutic targeting of liver inflammation and f ibrosis by nanomedicine

Nanomedicine constitutes the emerging field of medical applications for nanotechnology suchas nanomaterial-based drug delivery systems. This technology may hold exceptional potential for noveltherapeutic approaches to liver diseases. The specific and unspecific targeting of macrophages, hepaticstellate cells (HSC), hepatocytes, and liver sinusoidal endothelial cells (LSEC) using nanomedicine has beendeveloped and tested in preclinical settings. These four major cell types in the liver are crucially involvedin the complex sequence of events that occurs during the initiation and maintenance of liver inflammationand fibrosis. Targeting different cell types can be based on their capacity to ingest surrounding material,endocytosis, and specificity for a single cell type can be achieved by targeting characteristic structuressuch as receptors, sugar moieties or peptide sequences. Macrophages and especially the liver-residentKupffer cells are in the focus of nanomedicine due to their highly efficient and unspecific uptake of mostnanomaterials as well as due to their critical pathogenic functions during inflammation and fibrogenesis.The mannose receptor enables targeting macrophages in liver disease, but macrophages can also become activated by certain nanomaterials, such as peptide-modified gold nanorods (AuNRs) that render themproinflammatory. HSC, the main collagen-producing cells during fibrosis, are currently targeted usingnanoconstructs that recognize the mannose 6-phosphate and insulin-like growth factor II, peroxisomeproliferator activated receptor 1, platelet-derived growth factor (PDGF) receptor β, or integrins. Targetingof the major liver parenchymal cell, the hepatocyte, has only recently been achieved with high specificity bymimicking apolipoproteins, naturally occurring nanoparticles of the body. LSEC were found to be targetedmost efficiently using carboxy-modified micelles and their integrin receptors. This review will summarizeimportant functions of these cell types in healthy and diseased livers and discuss current strategies of cellspecifictargeting for liver diseases by nanomedicine.