New insights into the design of RNA delivery vectors
8 November 2021
What happens to gene delivery vectors when they enter the cell cytoplasm? This question had remained understudied, in particular in the case of polycationic vectors. Yet it may have a significant impact on the timing and localisation of the release of RNA or DNA molecules to be delivered.
The team of Prof. Julien Gautrot used polymer brushes to study this process and characterised for the first time the composition of the vector cytosolic interactome, the collection of macromolecules associating with polycationic vectors upon entry into the cytosol. They reported these results in the journal Nature Communications (https://www.nature.com/articles/s41467-021-26695-w). In the cytoplasm, RNA-vector complexes find a densely crowded environment in which competitive binding, in particular with cytosolic RNA, regulates their dissociation. Altering the chemical structure of vectors to modulate competitive binding results in improved retention of RNA and prolonged transfection efficacy.
In addition, proteomics analysis identifies a number of cytoplasmic proteins recruited at RNA-vector complexes, many of which are associated with translation and transcription (binding RNA and DNA molecules). How such interactions may alter the activity of corresponding macromolecular complexes (including ribosomal) and their function remains unknown, but this work raises the possibility that such interactions may underlie some of the off-target effects observed with polycationic vectors. Regulating such interactions will be essential to explore such phenomenon and for the design of new generations of polycationic vectors, based on polymer brushes, regulating cytoplasmic macromolecular interactions and sustained therapeutic efficacy.
Updated by: Julien Gautrot