Structural\nReorganizations and Nanodomain Emergence\nin Lipid Membranes Driven by Ionic Liquids

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