Ionic liquids for biomacromolecule purification: from molecular interactions to practical applications

Biomacromolecules, particularly proteins and nucleic acids, are fundamental to modern biotherapeutics, yet their downstream purification remains hindered by structural complexities and high-fidelity impurities. Ionic liquids (ILs), recognized as "designer solvents," offer a versatile solution through the rational engineering of cation-anion pairs to enable selective, reversible interactions while effectively discriminating against impurities. This review systematically examines the mechanisms underlying molecular interactions between biomacromolecule and ILs, emphasizing how cation scaffold engineering and anion selection modulate binding mode and strength with proteins and nucleic acids. We further explore the integration of ILs into diverse separation platforms, including extraction, chromatography, and functionalized membranes, focusing on applications in proteins and nucleic acids purification, which have demonstrated superior performance such as above 95% recovery for IgG in ILs-based extraction system, and over 90% recovery for RNA separation from complex cell lysates using IL-based chromatographic process. Finally, future research directions towards more rational design of the downstream process for biomacromolecules and to further expand the application of ILs across the entire manufacturing framework of biomacromolecules will be discussed. We hope this review will provide some useful guidance for design of next-generation IL-based purification systems capable of addressing the complexities of emerging biotherapeutics.