Single-molecule biosensing platform: helping sensors find the right signal
Climate change and pollution can affect health long before disease becomes visible. Heat, air pollution and other environmental stressors may trigger early changes inside the body, including immune responses. To understand these changes, researchers need sensitive and reliable ways to detect biological signals, such as proteins or biomarkers.
This is one of the ambitions of the Flagship Personalized, Real-Time Health Impact of Climate Change and Pollution. The Flagship develops technologies that can help connect environmental exposure to biological response. Within this broader program, the single-molecule biosensing platform focuses on one essential part of that challenge: how to recognize and measure specific biological signals in samples from the body. This is an important step towards future tools that could help monitor how environmental stressors affect health.
| The visual below shows how the platform moves from current biosensing approaches towards a more detailed way of understanding, selecting and optimizing aptamers for future biosensors. |
How does a sensor know what to look for?
To build a useful health sensor, one question comes first: how does the sensor recognize the molecule it needs to measure? A biosensor may need to detect a specific protein, biomarker or pathogen in a very small sample, such as blood, sweat, skin fluid or another biological sample. This requires a recognition molecule: a molecule that can find and bind to the right target. When the target is captured, the sensor can turn that binding event into a measurable signal.
Many biosensors currently use antibodies for this recognition step. Antibodies are powerful because they can bind very specifically to a target. But they are not always easy to generate, adapt or standardize for every molecule researchers may want to measure.
Researchers at TU Delft are exploring an alternative: aptamers. Aptamers are synthetic recognition molecules made from short strands of DNA or RNA. In this context, DNA and RNA are used not as genetic code, but as molecular material that can fold into shapes capable of recognizing specific targets. Because aptamers are chemically defined and can be engineered in the lab, they may offer a more flexible route for biosensor development. However, finding an aptamer that binds to a target is only the first step. For biosensing, researchers need more than binding. A useful recognition molecule must bind selectively, behave reliably and produce a signal that can actually be measured. It also needs to perform reliably in practical assay conditions, where many promising molecules may behave differently than expected.
| What is a biosensor? A biosensor is a device or system that detects a biological molecule, such as a protein or biomarker, and turns that detection into a measurable signal. . What is an antibody? An antibody is a protein that can recognize and bind to a specific target, such as a biomarker or pathogen. In many biosensors, antibodies are used as the part that “captures” the molecule the sensor is trying to detect. . What is an aptamer? An aptamer is a lab-made recognition molecule made from a short strand of DNA or RNA. It can fold into a shape that recognizes a specific target, such as a protein or biomarker. |
Aptamers are often selected as binders, but for biosensing we need more than binding. We need to understand how they move, how they change shape and how these molecular motions generate a reliable signal.
What makes this approach innovative?
This is where the single-molecule biosensing platform comes in. The team is developing a laboratory platform to understand, select and optimize aptamers for health-related applications. Using single-molecule fluorescence, researchers can study aptamers one molecule at a time instead of only measuring the average behavior of many molecules together.
This level of detail is important because aptamers are dynamic molecules. They can fold, bend, switch between different shapes and become more stable when they bind to a target. These movements are not just molecular details: they can determine whether an aptamer produces a strong biosensing signal or fails to give a useful response.
The platform therefore shifts the question from “does this aptamer bind?” to “does this aptamer behave in a way that makes it useful for sensing?” By connecting aptamer sequence, molecular motion, target binding and sensor performance, researchers can better understand why one aptamer works well in a sensor while another does not.
| What is single-molecule fluorescence? Single-molecule fluorescence is a method that uses light to follow individual molecules. Researchers label molecules with fluorescent markers and observe how they move, interact or change shape. This can reveal conformational switching, molecular heterogeneity and structural stabilization after target binding: behaviors that are often hidden when many molecules are measured together. |
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From trial and error to smarter discovery
Conventional aptamer discovery can still involve a lot of trial and error. Researchers may find molecules that bind to a target, but only later discover whether they are suitable for a real biosensor. This project aims to shift aptamer discovery from trial-and-error selection towards more rational, mechanism-guided engineering. First, single-molecule fluorescence helps reveal how aptamers work. Then, SPARXS is being developed to scale that understanding across many aptamer sequences in parallel.
While standard single-molecule methods allow researchers to examine selected aptamers in great detail, SPARXS could make it possible to compare many sequence variants under the same experimental conditions. This may help reveal which sequence features lead to useful sensing behavior, support faster optimization of aptamers for biosensing and help define design principles for future aptamer-based biosensors.
| What is SPARXS? SPARXS is a multiplexed single-molecule platform being developed to study many aptamer sequences in parallel while still keeping single-molecule detail. For aptamer research, this means researchers could compare many possible aptamers under the same conditions and see which ones behave best for sensing. |
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Why this matters for health
Sensitive and reliable molecular detection is important for early diagnosis, disease monitoring and personalised medicine. If successful, this platform could help accelerate the development of aptamer-based biosensors for biomedical research and future diagnostic applications.
It may also enable faster discovery of synthetic recognition molecules for clinically relevant proteins, biomarkers, pathogens or other health-related targets. In the longer term, aptamer-based sensing may contribute to more flexible and reproducible diagnostic technologies, including laboratory assays and potentially point-of-care testing.
Why Convergence matters
The project brings together single-molecule biophysics, molecular biology, nanotechnology, data analysis and biomedical application. The Delft contribution is centred on single-molecule fluorescence, aptamer mechanics, molecular engineering and multiplexed sequence-resolved screening.
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Within Convergence, this technical work can connect to biomedical and clinical expertise from Erasmus MC and Erasmus University Rotterdam, especially for identifying relevant health-related targets, defining practical biosensing needs and exploring future validation routes. This connection is important, because a biosensing platform only becomes useful if it is developed with real health questions in mind. Which targets matter? What level of sensitivity and specificity is needed? What kind of biosensor would be useful in practice? And what would be required for future validation?
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Technology and industry partners may also play a role in later stages, for example in assay development, automation and translation towards practical sensing formats. By combining molecular insight, platform development and biomedical input, the collaboration helps ensure that the technology is developed with future health applications in mind from an early stage.
Part of the Flagship
The single-molecule biosensing platform is part of the Flagship Personalized, Real-Time Health Impact of Climate Change and Pollution. Within this broader program, the project focuses on one of the smallest but most important parts of future sensing technologies: the molecule that recognizes the target and helps generate a reliable signal. Read more about the Flagship: Personalized, Real-Time Health Impact of Climate Change and Pollution.