Engineering microenvironmental sensitive devices for targeted therapies

With rapidly progressing rational design of synthetic devices, synthetic biology has promised ground-breaking novel solutions in industrial and environmental technologies. While microorganisms’ re-engineering has raised the potential of manufacturing industries for production of several improved biochemical, bioplastics and biofules as alternatives to oil-derived materials, biomedical applications were initially directed toward the development of more cost-effective and less time-consuming strategies for drug production (i.e. engineering yeast to produce the antimalarial drug Artemisin). However, in the past few years an increasing attention to use synthetic biology for tailoring personalised therapies has raised challenges that synthetic biologists need to face to explore this tremendous opportunity. Among them, drug-target specificity and robust control of circuits activity are demanding tasks. As a result, mammalian synthetic biology has focused on building high-precision control devices that respond to endogenous cues to perform programmed responses. The key being, to use biomarkers that define intrinsic characteristic of a disease, thus allowing discrimination between healthy and unhealthy tissues/cells. For example, it has been proven that cancer cells show different microRNA signatures from the healthy counterpart. This notion was used to create ad hoc sensing-actuation devices based on microRNA classifiers, that are capable of distinguishing cervix adenocarcinoma cells from other cell lines, and that initiate a programmed transcriptional response in targeted cells. The advantage of this type of devices is two-fold. First, microRNA signatures can be easily re-adapted to the cell line/tissue of interest, thus tailoring the therapy. Second, by rewiring the output, the synthetic networks can trigger outcomes of interest, spanning from in vitro and in vivo mapping, to selective killing, to enhanced immune-response. Further, the efficacy of microRNA classifiers to fine tune the activity of RNA-based synthetic devices has been proven, which hold great promises in biomedical applications for their low immunogenicity, long-term expression, and low risk of genetic integration in the host genome. Next will be to expand the artillery of endogenous signals. We expect proteins and mRNAs to be the candidate biomarkers to tune synthetic networks’ activity, and to open the possibility of new landscapes of personalised treatments.