Structural Reorganizations and Nanodomain Emergence in Lipid Membranes Driven by Ionic Liquids

Ionic liquids (ILs) have promising applications in pharmaceuticals and green chemistry, but their use is limited by toxicity concerns, mainly due to their interactions with cell membranes. This study examines the effects of imidazolium-based ILs on the microscopic structure and phase behavior of a model cell membrane composed of zwitterionic dipalmitoylphosphatidylcholine (DPPC) lipids. Small-angle neutron scattering and dynamic light scattering reveal that the shorter-chain IL, 1-hexyl-3-methylimidazolium bromide (HMIM[Br]), induces the aggregation of DPPC unilamellar vesicles. In contrast, this aggregation is absent with the longer alkyl chain IL, 1-decyl-3-methylimidazolium bromide (DMIM[Br]). Instead, DMIM[Br] incorporation leads to the formation of distinct IL-poor and IL-rich nanodomains within the DPPC membrane, as evidenced by X-ray reflectivity, differential scanning calorimetry, and molecular dynamics simulations. The less evident nanodomain formation with HMIM[Br] underscores the role of hydrophobic interactions between lipid alkyl tails and ILs. Our findings demonstrate that longer alkyl chains in ILs significantly enhance their propensity to form membrane nanodomains, which is closely linked to enhanced membrane permeability, as shown by dye leakage measurements. This heightened permeability likely underlies the greater cytotoxicity of longer-chain ILs. This crucial link between nanodomains and toxicity provides valuable insights for designing safer, more environmentally friendly ILs, and promoting their use in biomedical applications and sustainable industrial processes.