Charting Metabolism Heterogeneity by Nanostructure Imaging Mass Spectrometry: From Biological Systems to Subcellular Functions.

The study of metabolism heterogeneity is essential to understand the role of metabolites in supporting and regulating biological functions. To this end, several mass spectrometry imaging (MSI) approaches have been proposed for the detection of small molecule metabolites. However, high noise from the ionization matrix and low metabolome coverage hinder their applicability for untargeted metabolomics studies across space. In this context, nanostructure imaging (/initiator) mass spectrometry (NIMS) and NIMS with fluorinated gold nanoparticles (f-AuNPs) are attractive strategies for comprehensive MSI of metabolites in biological systems, which can provide heterogeneous metabolome coverage, ultrahigh sensitivity, and high lateral resolution. In particular, NIMS with f-AuNPs permits the simultaneous detection of polar metabolites and lipids in a single and cohesive analytical session, thus allowing the systems-level interpretation of metabolic changes. In this Perspective article, we discuss the use of NIMS and f-AuNPs in the exploration of metabolism heterogeneity and provide a critical outlook on future applications of this technology for revealing the metabolic architecture that supports biological functions in health and disease, from whole organisms to tissues, single cells, and subcellular compartments.