Description du projet
Des nanostructures et des réseaux hybrides fonctionnels contrecarrent les dysfonctionnements naturels
De nombreuses voies cellulaires reposent sur des nanostructures au sein des cellules. Ces voies assurent les fonctions cellulaires normales et protègent les cellules contre les agents pathogènes nanométriques. La compréhension de ces mécanismes de traitement à l’échelle nanométrique liés aux nanostructures endogènes permettra de concevoir des nanostructures synthétiques ou hybrides capables de reproduire les étapes du traitement cellulaire. Le projet FunctionalNanoTher, financé par le CER, se penchera sur les mécanismes de portes à l’échelle nanométrique supposés jouer un rôle dans la défense cellulaire. Il part de l’hypothèse que certains assemblages moléculaires agissent comme des «codes d’accès», autorisant l’accès intracellulaire aux réseaux biomoléculaires incorporés dans les nanostructures. Le projet tentera de reproduire ces interactions de «portes» pour des thérapies fonctionnelles à l’échelle nanométrique dans l’environnement tumoral.
Objectif
We will develop new functional nanoscale medicines that engage and co-operate with cellular pathways that were designed to process and extract useful information from endogenous nanostructures, as well as protect the organism from nanoscale pathogens. We show how functional hybrid nanostructures, part-synthetic and part-cell-derived biomolecular condensate, elicit the full repertoire of cellular processing steps. In particular the enabling of highly efficient escape from endosomes and providing intracellular access to nanostructure embedded biomolecular networks. We show how cellular defences include nanoscale molecular interaction gating mechanisms that grant access on the formation of prescribed molecular assemblies that act as ‘access key codes’. The assembled molecular interactions at these gates may be captured and analysed using time-resolved spatially localized chemical reactions within the cell, and the enabling assemblies analysed in molecular detail. The cell-derived condensate portion of the hybrid particles may be re-engineered to incorporate foreign proteins and RNAs, while retaining overall function, and the new biomolecules can then be delivered to intracellular locations with their function intact. These advances make it possible to understand the connection between nanostructure architecture and function, and thereby open the pathway to recapitulate the functional nanostructures using purely preparative methods. To apply these systems we first propose to use functional nanostructures to deliver specifically optimised mRNA for Covid-19 spike protein into the cell, optimising mRNA metabolism to benefit from endogenous intracellular access. We then propose to engineer and deliver cooperative networks of multiple mRNA, with the prospect of being able to develop functional nanoscale therapies that can counter more extended dysfunctional networks such as those found in the tumour microenvironment.
Champ scientifique
Mots‑clés
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thème(s)
Régime de financement
HORIZON-ERC - HORIZON ERC GrantsInstitution d’accueil
4 Dublin
Irlande