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

Abstract: The exceptional physicochemical properties and versatile biological activities of ionic liquids (ILs) have propelled their potential applications in various industries, including pharmaceuticals and green chemistry. However, their widespread use is limited by concerns over toxicity, particularly due to 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) lipid. Small-angle neutron scattering and dynamic light scattering reveal that the shorter chain IL, 1-hexyl-3-methylimidazolium bromide (HMIM[Br]), induces 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 simulation. 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 and increase membrane permeability, directly correlating with higher cytotoxicity. 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.