Impact of net charge, targeting ligand amount and mRNA modification on the uptake, intracellular routing and the transfection efficiency of mRNA lipopolyplexes in dendritic cells

GalNAc- or Mannose-PEG-Functionalized Polyplexes Enable Effective Lectin-Mediated DNA Delivery

“…For active targeting, lectins (i.e., carbohydrate-binding proteins), such as the asialoglycoprotein receptor (ASGPR), or mannose receptors represent interesting targets due to their high degree of specificity . Targeting of ASGPR expressed on hepatocytes has already been subject of many studies. ,− ASGPR shows high affinity and specificity toward multiantennary galactose and N -acetyl galactosamine (GalNAc) and induces receptor-mediated endocytosis. , Whereas the first reported targeted gene delivery focused on natural ligands for targeting ASGPR, , artificial GalNAc ligands became extensively studied and were continuously optimized for improved nucleic acid transfer to hepatocytes. , This optimization resulted in the market approval of several direct ligand–siRNA conjugates for the treatment of rare diseases. − Mannose receptors, i.e., C-type lectins known for the recognition of mannose, fucose, and N -acetylglucosamine residues, have also been addressed by researchers for directed nucleic acid delivery to immune cells such as dendritic cells and macrophages, − which is particularly interesting for vaccination approaches and cancer immunotherapy. , …”