Descrizione del progetto
Nanostrutture e reti ibride funzionali che contrastano quelle naturali disfunzionali
Molti percorsi cellulari si basano su nanostrutture all’interno delle cellule, contribuendo alle normali funzioni cellulari e proteggendole dagli agenti patogeni di dimensioni nanometriche. La comprensione di questi meccanismi di elaborazione su scala nanometrica legati alle nanostrutture endogene consentirà di progettare nanostrutture sintetiche o ibride in grado di replicare le fasi di elaborazione cellulare. Il progetto FunctionalNanoTher, finanziato dal CER, si concentrerà sui meccanismi di gating su scala nanometrica che, secondo quanto ipotizzato, svolgerebbero un ruolo attivo nella difesa cellulare. L’ipotesi propone che alcuni assemblaggi molecolari agiscano in qualità di «codici di accesso», garantendo l’accesso intracellulare alle reti biomolecolari incorporate nelle nanostrutture. Il progetto cercherà di replicare queste interazioni di «gating» per implementare terapie funzionali su scala nanometrica nell’ambiente tumorale.
Obiettivo
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.
Campo scientifico
Parole chiave
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-ERC - HORIZON ERC GrantsIstituzione ospitante
4 Dublin
Irlanda