Description du projet
Des nanoparticules pour améliorer la tolérance immunitaire
Les nanoparticules lipidiques ionisables (Ionisable lipid nanoparticles, iLNP) sont un type de système de nanovecteurs à base de lipides, conçu pour délivrer de l’ARN ou de l’ADN à des cellules cibles. Ces nanoparticules ont fait l’objet d’une attention particulière dans le domaine de l’administration de médicaments, de la thérapie génique et des vaccins à base d’ARNm. Alors que leur activité adjuvante semblait provenir uniquement des lipides ionisables, des découvertes récentes remettent en cause cette notion. Les iLNP vides sans ARNm induisent une maturation homéostatique et non immunogène des cellules dendritiques. Financé par le Conseil européen de la recherche, le projet LNP-DECODE vise à approfondir l’idée d’utiliser les iLNP pour induire la tolérance plutôt que l’immunité, en particulier contre les allergènes et les antigènes auto-immuns. Le développement de biomarqueurs permettant de distinguer les cellules dendritiques matures tolérogènes des cellules dendritiques matures immunogènes facilitera la conception de LNP plus sûres et plus polyvalentes pour une utilisation clinique.
Objectif
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.
Champ scientifique
Mots‑clés
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régime de financement
HORIZON-ERC-POC - HORIZON ERC Proof of Concept GrantsInstitution d’accueil
9052 ZWIJNAARDE - GENT
Belgique