Manganese-coordinated mRNA vaccines with enhanced mRNA expression and immunogenicity induce robust immune responses against SARS-CoV-2 variants.

It is urgent to develop more effective mRNA vaccines against the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants owing to the immune escape. Here, we constructed a novel mRNA delivery system [IC8/Mn lipid nanoparticles (IC8/Mn LNPs)]with high immunogenicity, via introducing a stimulator of interferon genes (STING) agonist [manganese (Mn)] based on a newly synthesized ionizable lipid (IC8). It was found that Mn can not only promote maturation of antigen-presenting cells via activating STING pathway but also improve mRNA expression by facilitating lysosomal escape for the first time. Subsequently, IC8/Mn LNPs loaded with mRNA encoding the Spike protein of SARS-CoV-2 Delta or Omicron variant (IC8/Mn@D or IC8/Mn@O) were prepared. Both mRNA vaccines induced substantial specific immunoglobulin G responses against Delta or Omicron. IC8/Mn@D displayed strong pseudovirus neutralization ability, T helper 1-biased immune responses, and good safety. It can be concluded that IC8/Mn LNPs have great potential for developing Mn-coordinated mRNA vaccines with robust immunogenicity and good safety.