On April 17^th, 2024, a research article was published in Nature entitled "Digital colloid-enhanced Raman spectroscopy by single-molecule counting." Designed to overcome the long-standing challenge of quantitative reproducibility in the field of surface-enhanced Raman spectroscopy (SERS), digital colloid-enhanced Raman spectroscopy (dCERS) was developed based on the principle of single-molecule counting, achieving reproducible quantitative detection of target molecules at ultra-low concentrations and laying the critical foundation for the broad application of SERS.

Background

Raman spectra were discovered by Chandrasekhara Venkata Raman in 1928, who was awarded the 1930 Nobel Prize in Physics. Owing to inherently unique vibrational characteristics of molecules, this spectroscopy provides a “fingerprint” of individual molecular species, which thereby can be used for their identification. As no external labels are needed, this method has since found wide application in physics, chemistry, biology, geology, medicine, national defense and public security.

However, Raman signals are intrinsically weak, and so signal enhancement is crucial. Surface-enhanced Raman spectroscopy (SERS) was first discovered in 1974 by Martin Fleischmann at the University of Southampton. The phenomenon was explained in 1977 from an electromagnetic perspective by David L. Jeanmaire and Richard P. Van Duyne from Northwestern University and as owing to a charge-transfer effect by M. Grant Albrecht and J. Alan Creighton from the University of Kent. The surface enhancement of the signal can be so significant that single molecules can be detected with SERS, and so has been considered as possibly worthy of a second Nobel Prize. This area is indeed a vigorous area of research, as substrates with various surface morphologies have been developed with the goal of even higher enhancements, including nanostars, nanourchins, nanoflowers, nanoforests, among others. Nanostructures like tips and gaps were specifically created through wet chemistry and chip fabrication methods to produce intense electromagnetic hotspots to enable the detection of molecules at ultra-low concentrations.

However, although the field has continued to grow, there has emerged a persistent problem that has plagued all research: the signal intensities at low concentrations have been significantly irreproducible. Thus, while single molecules can be detected, accurate quantification of solution concentrations has heretofore not been possible. Thus, obtaining a platform that satisfies the dual requirements of high signal enhancement and reproducible quantification has remained a long-standing goal within the SERS community. Indeed, this issue has remained a major bottleneck that cannot be solved with any currently known technical frameworks.