Project description
Functional hybrid nanostructures and networks counteract dysfunctional natural ones
Many cellular pathways rely on nanostructures within the cells. These pathways subserve normal cellular functions and protect cells from nanoscale pathogens. Understanding these nanoscale processing mechanisms related to endogenous nanostructures will enable engineering of synthetic or hybrid nanostructures that can replicate cellular processing steps. The ERC-funded FunctionalNanoTher project will focus on nanoscale gating mechanisms hypothesised to play a role in cellular defence. It is hypothesised that certain molecular assemblies act like ‘access key codes’, granting intracellular access to nanostructure-embedded biomolecular networks. The project will attempt to replicate these ‘gating’ interactions for functional nanoscale therapies in the tumour environment.
Objective
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.
Fields of science
Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
4 Dublin
Ireland