  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.
