We propose to undertake a new challenge: the control of gene expression systems by physico-chemical means to achieve the following objectives: i) developing robust tools for spatio-temporal control of protein expression; ii) understanding the role of micro-environmental factors in gene regulation; and iii) constructing and implementing in vivo smart nanomachines able to express active molecules in response to a stimulus and deliver them to a targeted cell. First, various biochemical processes (transcription, translation) will be controlled by light in vitro, based on photo-induced conformational changes of nucleic acids (DNA, RNA) and chromatin. Based on conformational changes rather than specific template-protein interaction, and combined with microfluidic methodologies, this novel approach will provide a ubiquitous tool to address gene expression using light regardless of the sequence, with unique control and spatio-temporal resolution. Second, by reconstituting photo-responsive gene expression systems in well-defined giant liposomes, we will study the dynamics of gene expression in response to light stimulation. This will allow us to establish the respective roles of the membrane (surface charge, permeability) and of the inner micro-environment composition (viscosity, molecular crowding). Third, we will develop stable, long-circulating polymer nanocapsules (polymersomes) encapsulating a gene expression material that can be triggered by light and/or molecules of biological interest. In response to the signal, an exogenous, potentially immunogenic enzyme will be expressed inside the protecting nanocapsule to locally and catalytically convert a non toxic precursor present in the medium into a cytotoxic drug that will be delivered to a cell (e.g. a cancer cell). This new concept of triggerable gene-carrying nanomachines with unique amplification capacity of drug secretion shall open new horizons for the development of smart biological probes and future therapeutics.
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