MetaCARS: observing and identiying individual molecules at ultrahigh speeds

Being able to detect and track a single molecule with light is a capability that has revolutionized science. Developed over 30 years ago, single-molecule spectroscopy is now foundational to many fields. It allows us to understand the inner workings of enzymes, which is critical for drug development, and to study the key steps of chemical reactions, which helps advance industrial processes. This approach is also the basis for modern nucleic acid sequencing, a cornerstone of personalized medicine and disease diagnosis. The technique's enormous scientific and societal impact was recognized with the 2014 Nobel Prize in Chemistry. Despite its success, this technology has clear limitations that have held back further progress. Most methods rely on fluorescent tags, which can alter a molecule's natural behavior and introduce measurement errors. Label-free methods, which are preferred, are typically either too slow or cannot determine a molecule's chemical identity. Currently, no label-free optical technique can identify individual molecules faster than a millisecond—a speed that is too slow for studying fast chemical dynamics or performing rapid molecular sequencing. This technological gap has stalled advances in key areas like enzymatic catalysis and genomic screening. In this program, we develop MetaCARS, a new molecular sensing technology that can identify and monitor individual molecules at the microsecond scale, accelerating the state-of-the-art by more than three orders of magnitude. By combining the latest advances in nonlinear Raman spectroscopy and nanophotonics, this new approach opens the next chapter in single-molecule research. We will conceptualize, build, and validate the MetaCARS technology and apply it to follow the rapid reaction dynamics of unlabeled, single proteins for the first time.