Attomole enantiomeric discrimination of small molecules using an achiral SERS reporter and chiral plasmonics

Biologically important molecules span a size range from very large biomacromolecules, such as proteins to small metabolite molecules. Consequently, spectroscopic techniques which can detect and characterize the structure of inherently chiral biomolecules over this range of scale at the femtomole level are necessary to develop novel biosensing and diagnostic technologies. Nanophotonic platforms uniquely enable chirally sensitive structural characterisation of biomacromolecules at this ultrasensitive level. However, they are less successful at achieving the same level of sensitivity for small chiral molecules, with less than nanomole typical. This poorer performance can be attributed to the optical response of the platform being sensitive to a much larger volume of the near field than is occupied by the small molecule. Here we show that by combining chiral plasmonic metasurfaces with Raman reporters, which can detect changes in electromagnetic environment at molecular dimensions, chiral discrimination can be achieved for attomole quantities of a small molecule, the amino acid cysteine. The signal-to-noise, and hence ultimate sensitivity, of the measurement can be further improved by combining the metasurfaces with gold achiral nanoparticles. This indirect enantiomeric detection is 9 orders of magnitude more sensitive than strategies relying on monitoring the Raman response of target chiral molecules directly. Given the generic nature of the phenomenon,this study provides a framework for developing novel technologies for detecting a broad spectrum of small biomolecules, which would be useful tools in the field of metabolomics.