Enhanced surface nanoanalytics of transient biomolecular processes

Fundamental knowledge of the physical and chemical properties of biomolecules is key to understanding molecular processes in health and disease. Bulk and single-molecule analytical methods provide rich information about biomolecules but often require high concentrations and sample preparation away from physiologically relevant conditions. Here, we present the development and application of a lab-on-a-chip spray approach that combines rapid sample preparation, mixing, and deposition to integrate with a range of nanoanalytical methods in chemistry and biology, providing enhanced spectroscopic sensitivity and single-molecule spatial resolution. We demonstrate that this method enables multidimensional study of heterogeneous biomolecular systems over multiple length scales by nanoscopy and vibrational spectroscopy. We then illustrate the capabilities of this platform by capturing and analyzing the structural conformations of transient oligomeric species formed at the early stages of the self-assembly of a-synuclein, which are associated with the onset of Parkinson's disease.