Bioorthogonal Signal Transduction: Chemical Exponential Signal Amplification for Applications in Biosensing

Diagnostic testing is challenging when the targeted compounds are present in extremely small amounts. Sophisticated laboratories are required to detect low levels in samples, which makes the tests expensive and limits their availability. If the signal from targeted compounds could be amplified, some tests could become available in homes and smaller clinics. This project will make detection easier by amplifying signals using simple chemical reactions. The project will demonstrate that one chemical reaction can generate several new reactive molecules, which can then trigger more reactions. As the reactions continue, the signal will grow rapidly until it becomes easy to detect optically. This technology may support a wide range of applications, including at-home disease tests, environmental and food safety monitoring, and rapid response tools for public health and security. The project outcomes will make advanced diagnostic capabilities more accessible, affordable, and practical in everyday settings. A central challenge in biosensing and diagnostics is that many target analytes are present at extremely low concentrations, requiring advanced instrumentation for detection. This requirement leads to high costs and limits many assays to specialized laboratory settings. Exponential signal amplification offers an alternative strategy by enhancing detection sensitivity while reducing instrumental requirements, but existing approaches largely rely on enzymes and complex reaction conditions. This project will develop a purely chemical approach to exponential signal amplification for biosensing applications. The core concept is a self-propagating chemical reaction in which a single triggering event generates multiple reactive species, producing an amplification cascade that can be coupled to an optical readout. To ensure compatibility with biologically relevant molecules, the design relies on rapid and selective bioorthogonal dissociative reactions. The project will establish the principles governing this chemical amplification strategy and evaluate its performance in biosensing formats. The approach will be implemented for the detection of protein and RNA analytes, enabling assessment of sensitivity, specificity, and practical applicability. The project outcomes are expected to introduce a new class of enzyme-free amplification methods with broad relevance to biosensing, diagnostics, and biological research. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria. NSF Award ID: 2531668 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Raphael Franzini | Institution: University of Utah, SALT LAKE CITY, UT | Award Amount: $523,361 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2531668 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2531668.html