Polyethyleneimine (PEI) has long been considered as “golden standard” for polymeric gene delivery carriers. To get a better understanding on the molecular basis of PEI cytotoxicity, dynamic light scattering, zeta-potential measurement, fluorescence emission, Froster resonance energy transfer and anisotropy measurement were conducted to reveal the interaction between PEI and dimyristoylphosphatidylcholine (DMPC) liposome and the influence on the structural properties of the membrane. PEI was found to bind onto the surface of the liposome, inducing an aggregation of the vesicle and an increase in surface potential at low PEI concentration up to 0.05 mg mL−1. A further increase in PEI concentration made little change on the surface potential, however reduced the aggregation of the vesicle due to the repulsion between the adsorbed PEI chains. PEI binding slightly increased the fluidity of lipid in interface region and decreased its packing density, and thus resulted in an enhanced leakage of calcein through the membrane. The polymer size played an important role in PEI-DMPC liposome interaction. PEI of higher molecular weight was more favorable to interact with DMPC and more efficient to perturb the structural properties of the membrane.
