Ultrasensitive Raman Detection of Biomolecular Conformation at the Attomole Scale using Chiral Nanophotonics

Abstract Understanding the function of a biomolecule hinges on its 3D conformation or secondary structure. Chirally sensitive, optically active techniques based on the differential absorption of UV–vis circularly polarized light excel at rapid characterisation of secondary structures. However, Raman spectroscopy, a powerful method for determining the structure of simple molecules, has limited capacity for structural analysis of biomolecules because of intrinsically weak optical activity, necessitating millimolar (mM) sample quantities. A breakthrough is presented for utilising Raman spectroscopy in ultrasensitive biomolecular conformation detection, surpassing conventional Raman optical activity by 15 orders of magnitude. This strategy combines chiral plasmonic metasurfaces with achiral molecular Raman reporters and enables the detection of different conformations (α‐helix and random coil) of a model peptide (poly‐L/D‐lysine) at the ≤attomole level (monolayer). This exceptional sensitivity stems from the ability to detect local, molecular‐scale changes in the electromagnetic (EM) environment of a chiral nanocavity induced by the presence of biomolecules using molecular Raman reporters. Further signal enhancement is achieved by incorporating achiral Au nanoparticles. The introduction of the nanoparticles creates highly localized regions of extreme optical chirality. This approach, which exploits Raman, a generic phenomenon, paves the way for next‐generation technologies for the ultrasensitive detection of diverse biomolecular structures.