Desalting strategies for native mass spectrometry.

In native mass spectrometry (MS) salts are indispensable for preserving the native structures of biomolecules, but detrimental to mass sensitivity, resolution, and accuracy. Such a conflict makes desalting in native MS more challenging, distinctive, and sample-dependent than in peptide-centric MS. This review first briefly introduces the charged residue mechanism whereby native-like gaseous protein ions are released from electrospray droplets, revealing a higher degree of salt adduction than denatured proteins. Subsequently, this review summarizes and explores the existing strategies, underlying mechanisms and future perspectives of desalting in native MS. These strategies mainly focus on buffer exchange into volatile salts (offline and online approaches), addition of solution additives (e.g., anion, supercharging reagent, solution phase chelator and amino acid), use of submicron electrospray emitters (down to 60 nm), and other potential approaches (e.g., induced and electrophoretic nanoelectrospray ionization). The strategies of online buffer exchange and using nanoscale electrospray emitters are highlighted. This review would not only be a valuable addition to the field of sample preparation in MS, but would also serve as a beginner's guide to desalting in native MS.