Nanotechnology: flexible biosensors with modular design

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Biosensors play a key role in medical research and diagnostics. At present, however, they generally have to be specially developed for each application. A team led by LMU chemist Philip Tinnefeld has developed a general, modular strategy for designing sensors that can be easily adapted to various target molecules and concentration ranges. As the researchers report in the journal Nature Nanotechnology, their new modular sensor has the potential to significantly accelerate the development of new diagnostic tools for research.

The sensor uses a DNA origami scaffold, which consists of two arms connected by a molecular “hinge.” Each arm is tagged with a fluorescent dye, and the distance between the tags is recorded by means of fluorescence resonance energy transfer (FRET). In a closed state, the two arms are parallel; when the structure opens, the arms fold out to form an angle of up to 90°. “As a result of this large conformational change, the fluorescence signal also changes substantially,” explains Viktorija Glembockyte, senior author of the study. “This allows signals to be measured with considerably greater clarity and precision than in systems with small conformational changes.”

Cooperative effects

The origami scaffold can be equipped with docking sites for various biomolecular targets such as nucleic acids, antibodies, and proteins. Whether the sensor is open or closed depends on the binding of the respective target molecule to the origami scaffold. The sensor can thus be deliberately adapted and optimized through the use of additional binding sites or stabilizing DNA strands. “It’s relatively easy to design the origami such that several molecular interactions between target molecule and sensor are queried simultaneously,” explains Tinnefeld. “These multiple bonds lead to interesting cooperative effects which make it possible to specifically control the sensitivity of the sensor without intervening in the biomolecular interactions themselves – that is to say, the strength with which the target molecule docks to its binding site. This flexibility is a major advantage of our system.”

The researchers plan to further optimize the sensor in the future for biomedical and other applications. A possible field of application could be sensors that monitor various parameters and release active agents under certain conditions, says Tinnefeld

L. Grabenhorst et al.: Engineering Modular and Tunable Single Molecule Sensors by Decoupling Sensing from Signal Output. Nature Nanotechnology 2024