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.