Descrizione del progetto
Nanoparticelle per la tolleranza immunitaria
Le nanoparticelle lipidiche ionizzabili (iLNP, ionisable lipid nanoparticle) sono un tipo di sistema nanovettore a base lipidica progettato per la somministrazione di RNA o DNA alle cellule bersaglio. Queste nanoparticelle hanno attirato notevole attenzione in ambito di somministrazione controllata dei farmaci, terapia genica e vaccini a base di mRNA. Sebbene la loro attività adiuvante sembri derivare esclusivamente dai lipidi ionizzabili, recenti scoperte mettono in discussione questa ipotesi; le iLNP vuote, senza mRNA, inducono una maturazione omeostatica e non immunogenica delle cellule dendritiche. Finanziato dal Consiglio europeo della ricerca, il progetto LNP-DECODE si propone di esplorare l’idea di utilizzare le iLNP al fine di indurre tolleranza piuttosto che immunità, in particolare contro gli allergeni e gli antigeni autoimmuni. Lo sviluppo di biomarcatori volti a distinguere le cellule dendritiche mature tollerogeniche da quelle immunogeniche agevolerà la progettazione di LNP più sicure e versatili ai fini dell’utilizzo clinico.
Obiettivo
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.
Campo scientifico
Parole chiave
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-ERC-POC - HORIZON ERC Proof of Concept GrantsIstituzione ospitante
9052 ZWIJNAARDE - GENT
Belgio