Expanding Spatial Metabolomics Coverage with Lithium-Doped Nanospray Desorption Electrospray Ionization Mass Spectrometry Imaging

Spatial metabolomics has emerged as a powerful tool capable of revealing metabolic gradients throughout complex heterogeneous tissues. While mass spectrometry imaging (MSI) technologies designed to generate spatial metabolomic data have improved significantly over time, metabolite coverage is still a significant limitation. It is possible to achieve deeper metabolite coverage by imaging in positive and negative polarities or imaging several serial sections with different targeted biomolecular classes. However, this significantly increases the number of tissue samples required for biological studies and reduces the capacity for larger sample cohorts. Herein, we introduce lithium-doped nanospray desorption electrospray ionization (nano-DESI) as a simple and robust method to increase spatial metabolomics coverage, which is achieved through enhancements to ionization efficiencies in positive ion mode for metabolites and lipids lacking basic moieties, and improved structurally diagnostic tandem mass spectra for [M + Li]