Impact of ionic liquids on protein fibrillation: A comprehensive review

Ionic liquids (ILs) have emerged as a versatile class of liquids with applications across diverse fields. Their unique properties arising from a diverse combination of ions allow the tuning of structure to serve a desired purpose. Beyond their broad applications, ILs have attracted increasing interest in protein science because of their ability to modulate protein structure, stability, and aggregation. This review provides an overview of how ILs influence protein amyloid formation, either inhibiting or promoting it depending on factors such as the type of cation and anion, alkyl chain length, hydrophobicity, charge distribution, concentration, and specific ion-protein interactions. Comparative studies are discussed to highlight the effects of IL concentration and specific ion-protein interactions, including cases where ion behaviour deviates from classical Hofmeister predictions. Unlike recent reviews that broadly discuss ILs in protein science, this review specifically focuses on protein amyloid formation by systematically classifying research reported over the last decade based on their cationic framework and critically comparing both amyloid-inhibiting and amyloid-promoting effects across diverse protein systems. In addition, the mechanistic insights emerging from these interactions highlight the potential of ILs as tunable excipients for protein stabilization, while emphasising the importance of biocompatibility and cytotoxicity considerations. Collectively, this review integrates current mechanistic understanding of IL-mediated protein amyloid formation and identifies the key molecular factors governing protein fibrillation, providing a comprehensive resource for future therapeutic and biomaterial research.