A single DNA origami nanostructure can act as a mass tag, making individual proteins visible to a laser-based microscope without any chemical labels or washing steps. This matters because current protein-detection methods—like ELISA or mass spectrometry—either break apart weak interactions during washing or miss low-abundance molecules entirely. Many diseases, including Alzheimer’s and cancer, involve subtle changes in protein shape, clustering, or chemical modifications that these tools cannot capture in real time. The project combines mass photometry, which weighs single molecules in solution, with programmable DNA scaffolds that amplify the signal from target proteins. This allows the platform to detect transient protein complexes and post-translational modifications directly in blood or serum, without disrupting their native state. If successful, the platform could transform early-stage diagnostic testing by spotting disease-relevant protein changes that current tests miss. It may also accelerate drug development by revealing how candidate drugs affect weak protein interactions in near-physiological conditions. The work is applied fundamental science—it builds a new tool for molecular analysis rather than targeting a specific disease, but its ability to monitor real-time protein behaviour could reshape how researchers study molecular mechanisms in health and disease.
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Proteins play a central role in cellular function and regulation, making them essential for understanding biological processes and the development of therapeutic interventions. Unlike nucleic acids, which benefit from amplification mechanisms for sensitive detection, proteins lack these intrinsic advantages, making their detection challenging. This difficulty originates in achieving the sensitivity, specificity, and molecular detail needed to characterise proteins fully. While current technologies have made strides in sensitivity and multiplexing, they predominantly focus on detecting the presence or absence of proteins. This binary perspective fails to account for the molecular state of biomarkers, such as oligomeric structure, post-translational modifications (PTMs), or integration into larger complexes. In many diseases, pathology arises not only from the abundance of specific proteins but also from changes in their interactions, associations, or modifications. For instance, phosphorylation events in proteins like p53 regulate its tumour-suppressive activity, while abnormal protein aggregation underlies conditions like Alzheimer’s disease. Traditional protein detection methods, such as enzyme-linked immunosorbent assays (ELISA), affinity purification, or mass spectrometry (MS), often require washing, chromatography, or labelling steps. While effective at reducing noise and improving specificity, these processes disrupt weak, or transient, interactions critical to protein function. For example, washing steps in ELISA cause low-affinity interactions to dissociate, while MS struggles with low abundance species. This challenge is especially prominent in complex biological media like serum or plasma, where detecting interactions in native, physiologically relevant environments remains difficult. These limitations restrict our understanding of disease mechanisms, impeding the discovery of subtle biomarkers associated with early-stage pathologies. This project addresses these challenges by combining mass photometry (MP) with programmable DNA nanotechnology. MP, an optical and label-free technique, allows real-time, quantitative mass measurement of single biomolecules, while DNA nanotechnology enables controlled and programmable manipulation of molecules with nanometre precision. By integrating these technologies, we will develop a multiplexed platform capable of detecting, quantifying, and characterizing proteins and their complexes under near-physiological conditions, capturing subtle interactions like PTMs and oligomerization without disrupting native protein behaviour. Leveraging DNA nanostructures to amplify mass signals and enhance detection sensitivity above background noise, the platform eliminates the need for sample preparation, washing, or labelling, preserving biomolecules in their native state and boosting detection of low-abundance species. This enables real-time analysis of weak and transient protein-protein interactions in near physiological conditions. With the capacity to measure multiple biomarkers simultaneously, the system offers comprehensive insights into complex biological systems, supported by built-in internal controls for reliable and reproducible results. We will validate the platform’s capabilities with case studies on disease-relevant biomarkers, including cancer biomarker profiling, phosphorylation detection, and analysis of protein oligomeric states, showcasing its ability to effectively address intricate biomolecular questions. The applications of this platform go beyond existing protein detection methods, addressing critical challenges in bioscience research and therapeutic development. By enabling programmable and multiplexed analysis without disruptive washing steps, the platform provides real-time insights into weak interactions, transient protein complexes, and functional modifications, redefining how molecular mechanisms are studied under native conditions. This equips researchers with tools to uncover subtle biological changes and drives innovation in drug discovery by identifying new therapeutic targets and improving drug efficacy evaluation in native environments, ultimately transforming our understanding of molecular mechanisms in health and disease.
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