A review of nanoscale LC-ESI for metabolomics and its potential to enhance the metabolome coverage

Liquid chromatography-electrospray ionisation-mass spectrometry (LC-ESI-MS) platforms are widely used to perform high throughput untargeted profiling of biological samples for metabolomics-based approaches. However, these LC-ESI platforms usually favour the detection of metabolites present at relatively high concentrations because of analytical limitations such as ion suppression, thus reducing overall sensitivity. To counter this issue of sensitivity, the latest in terms of analytical platforms can be adopted to enable a greater portion of the metabolome to be analysed in a single analytical run. Here, nanoflow liquid chromatography-nanoelectrospray ionisation (nLC-nESI), which has previously been utilised successfully in proteomics, is explored for use in metabolomic and exposomic research. As a discovery based field, the markedly increased sensitivity of these nLC-nESI platforms offer the potential to uncover the roles played by low abundant signalling metabolites (e.g. steroids, eicosanoids) in health and disease studies, and would also enable an improvement in the detection of xenobiotics present at trace levels in biological matrices to better characterise the chemical exposome. This review aims to give an insight into the advantages associated with nLC-nESI for metabolomics-based approaches. Initially we detail the source of improved sensitivity prior to reviewing the available approaches to achieving nanoflow rates and nanospray ionisation for metabolomics. The robustness of nLC-nESI platforms was then assessed using the literature available from a metabolomic viewpoint. We also discuss the challenging point of sample preparation which needs to be addressed to fully enjoy the benefits of these nLC-nESI platforms. Finally, we assess metabolomic analysis utilising nano scale platforms and look ahead to the future of metabolomics using these new highly sensitive platforms.