Innate immune sensing of two types of mRNA vaccine by a dendritic cell (DC), with RNA sensors shown in yellow, antigen in red, DC maturation factors in green, and peptide–major histocompatibility complex (MHC) complexes in light blue and red; an example lipid nanoparticle carrier is shown at the top right. A non-exhaustive list of the major known RNA sensors that contribute to the recognition of double-stranded and unmodified single-stranded RNAs is shown. Unmodified, unpurified (part a) and nucleoside-modified, fast protein liquid chromatography (FPLC)-purified (part b) mRNAs were selected for illustration of two formats of mRNA vaccines where known forms of mRNA sensing are present and absent, respectively. The dashed arrow represents reduced antigen expression. Ag, antigen; PKR, interferon-induced, double-stranded RNA-activated protein kinase; MDA5, interferon-induced helicase C domain-containing protein 1 (also known as IFIH1); IFN, interferon; m1Ψ, 1-methylpseudouridine; OAS, 2′–5′-oligoadenylate synthetase; TLR, Toll-like receptor.