mRNA-LNP vaccine strategies: Effects of adjuvants on non-parenchymal liver cells and tolerance

The liver, which plays pivotal roles in metabolism and immunity, often confers tolerance, suppressing immune responses to pathogens. Adjuvanted, lipid nanoparticle-encapsulated mRNA vaccines (mRNA-LNPs) offer a promising approach to overcome immune tolerance. In this study, the immunostimulatory activity of well-documented adjuvants, <i>i.e</i>., 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), resiquimod (R848), and polyinosinic:polycytidylic acid (Poly I:C), on non-parenchymal liver cells was determined. When co-applied with mRNA-loaded LNPs, these adjuvants enhanced immune responses at variable extents. Moreover, the efficiency of mRNA translation in the presence of cGAMP was comparable with the non-adjuvanted control. Repetitive co-application of adjuvants with mRNA-LNPs showed improvement in cellular responses when R848 or R848/cGAMP treatments were used. These findings emphasize the need to delineate the delicate balance between immunomodulatory properties and the efficiency of mRNA translation when selecting adjuvants for mRNA-LNP vaccines and offer insights on how to enhance immunity to infectious diseases and cancers that affect the liver.