LNP-DECODE · LNP-DECODE: Broadening the therapeutic window of LNP-based vaccination

The recent success of ionizable lipid nanoparticles (iLNPs) as vehicles for mRNA (mRNA-iLNP) as a safe and highly effective vaccine in the protection against SARS-CoV-2 pushed the lipid nanoparticle technology to the forefront of medicine and launched worldwide interest in their potential as a therapeutic vaccine against numerous pathogens or tumor antigens. Still, their mode of action remains largely a black box. One of the most remarkable properties of mRNA-LNPs is that they do not require any additional adjuvant, explaining for a large part their success. Current belief poses that their adjuvant activity originates from the ionizable lipids without any need for mRNA components. Our data challenge this belief as we found that empty, non-mRNA containing LNPs induce homeostatic, not immunogenic dendritic cell (DC) maturation. This observation has far-stretching clinical implications as it suggests that if one finds a reliable manner to incorporate antigens in a non-immunogenic fashion in LNPs, i.e. as peptides or non-immunogenic mRNA molecules, we can broaden the scope of LNPs from inducers of protective immunity to inducers of tolerance. The current project aims to explore this idea by testing the induction of tolerance against allergens and auto-immune antigens incorporated as peptide cargo within LNPs. In addition, we developed a unique toolbox with a set of biomarkers that distinguish tolerogenic from immunogenic mature DCs. In the current project, we want to validate whether we can use these biomarkers to monitor in vivo the effect of different types of LNPs on DCs and predict their capability to induce tolerance or immunity. We believe that these findings will be highly valuable to help rational design of the future generation of LNPs, guarantee a safer use in the clinic and potentially broaden their scope to inducers of tolerance.