The lipid nanoparticle (LNP) technology has enabled the clinical translation of RNA therapeutics, and in particular the role played by the LNPs in today's success story with the mRNA vaccines against COVID-19 has become a very hot topic. The idea that the LNPs do not only work as delivery vehicle, but that they are also the key mediator of the pro-inflammatory activity and associated adverse effects of these mRNA vaccines, is a recent lead of investigation. This project aims to better understand the adjuvant mechanisms of these LNPs, and ultimately to exploit this knowledge to come up with improved LNP designs for SARS-COV-2 mRNA vaccine development. The workpackages relate to the design and characterization of LNPs with variable compositions, followed by their preclinical testing in different cell- and mouse models. In particular, we want to study (i) how the cholesterol content of the LNP formulation impacts the innate immune reaction, and (ii) whether we can identify LNPs that show a reduced uptake in monocytes, as we hypothesize that these molecular and cellular interactions could play important roles in the pro-inflammatory response to mRNA LNP vaccines. We believe that this research project could not only lead to improved (at least safer) vaccine designs, but could also open up new opportunities to develop optimized LNPs for other mRNA-based therapeutics.