DNA nanodevices that can enter cells and quantitatively image the level of chemicals in organelles might find applications in medical diagnostics.
At the end of 2017, the field of DNA nanotechnology witnessed a leap forward when three papers were published showing the possibility of scaling up DNA origami structures at a cheaper cost than ever before1,2,3. In the short editorial that we published on that occasion4, we remarked how, although this certainly represented the overcoming of a major roadblock in the field, not every application requires micrometre-sized DNA structures. For biological applications, smaller and simpler structures are often preferable. Their small size aids cellular uptake, their flexibility offers the chance of exploring various conformations and stimuli-responsive conformational changes, and their modularity offers the possibility of adding different functionalities on the DNA scaffold. Elegantly engineered DNA nanodevices have been proposed as probes in molecular diagnostics, cell sensing, drug delivery and imaging applications5.
For example, small DNA duplexes have been designed to report on the concentrations of secondary metabolites in living cells and living organisms. These probes generally comprise fluorescence moieties responsive to particular chemicals, an internal standard for ratiometric quantification of the chemicals and possibly a targeting label to direct the DNA structures to specific organelles within the cells.
ChloropHore, the probe described in the paper published in the current issue of Nature Nanotechnology, measures the pH and the Cl− content within single lysosomes simultaneously and independently. Plotting these concentration values on a two-dimensional map, the researchers obtained a chemical fingerprint of the lysosomes within cells, which led them to discover different organelle chemotypes. In particular, they identified a subclass of lysosomes that disappears in individuals suffering from the Niemann–Pick A, B or C diseases — a group of lysosomal storage disorders — and re-appears upon treatment of the cells with a known drug for these diseases.
From the same laboratory come the evocatively named DNA probes CalipHluor6 and cHOClate7, which measure Ca2+/pH and HOCl/pH in lysosomes and phagosomes, respectively. This series of sensors offers the opportunity of drawing a precise picture of the chemical status of organelles in specific circumstances, with ramifications for the fundamental understanding of cell biology and for possible medical applications. ChloropHore shows the possibility of using these devices to link the chemical identity of patients’ cells and organelles to their health, and to monitor the effect of specific drugs and therapies. In other words, it introduces DNA nanotechnology into the world of personalized medicine.
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DNA nanostructures fingerprint cellular organelles. Nature Nanotech 14, 99 (2019). https://doi.org/10.1038/s41565-019-0384-3