How to overcome the protein corona problem in surface-enhanced Raman scattering (SERS) analyses of cell culture media

In bioanalysis, where its use has expanded over the last decades, surface-enhanced Raman scattering (SERS) still encounters a major issue: the protein corona. This corona forms due to the adsorption of serum proteins onto the SERS substrates and stabilises the latter while competing with the analyte of interest for its surface.
Consequently, this work focussed on the development of new SERS sample preparations able to overcome the protein corona and that were applied to the analysis of neurotransmitters in cell culture media. First, the pre-aggregation of a colloidal gold SERS substrate was considered in order to get around the stabilisation problem. Then, an original device was developed, consisting of a cell culture insert with a low molecular weight cut-off (MWCO) ultracentrifugation membrane glued under it. The MWCO was selected in order to let small analytes diffuse through the membrane while retaining proteins of larger sizes. The device was placed in a multi-well plate above a solid SERS substrate and the spectra were acquired with a handheld Raman spectrophotometer through the bottom of the plate.
In addition to effective protein removal, the non-destructive, non-invasive and biocompatible character of this device makes it appealing and promising in the field of SERS cellular analysis.