Ionic liquids in proteomics: advances in protein solubilization, stabilisation, and mass spectrometry compatibility

Ionic liquids, a class of organic salts with low volatility, tunable polarity, and strong solvation ability, are emerging as valuable tools in proteomics.Traditional surfactants, such as sodium dodecyl sulfate and urea, while effective at disrupting proteins, can interfere with enzymatic digestion and mass spectrometry analysis, limiting their utility in sensitive workflows.In contrast, ionic liquids provide highly customizable solvent environments that not only enhance protein solubility but also help preserve native structures, thereby supporting improved downstream analytical compatibility.Recent advances have demonstrated the effectiveness of ionic liquids in solubilising membrane-bound and aggregated proteins, enhancing proteolytic digestion, and improving peptide recovery for mass spectrometry workflows.Taskspecific ionic liquids with optimised ion-pairing chemistry and reduced viscosity enable analysis of challenging targets such as integral membrane proteins and low-input proteomes.Beyond their role in protein extraction and digestion, ionic liquids also show promise as stabilisers in protein formulation and storage, offering unique opportunities for maintaining structural integrity during handling and long-term preservation.Their biocompatibility and tunability reduce sample loss, minimise ion suppression, and improve quantification of low-abundance peptides.This review summarises recent advances in ionic liquid applications in proteomics, highlights mechanistic insights into protein interactions, and discusses current challenges and future directions for ionic liquid-based bioanalytical workflows