<i>cis</i> – <i>trans</i> Geometrical Isomerism in Dioleoylphosphatidylcholine Governs Liposome Elasticity and siRNA Delivery Efficiency to MCF-7 Cells

In biomedical research, the microscopic elasticity of liposomes plays an important role in cellular uptake. The unsaturation in the lipid acyl chain and the geometrical isomerism of these double bonds are crucial players in modulating liposomal elasticity. Herein, we used AFM nanoindentation force spectroscopy, MD simulation, and Förster resonance energy transfer (FRET) measurements to probe the microelastic properties of four liposomes, including saturated dipalmitoylphosphatidylcholine (DPPC), monounsaturated phosphatidylcholine (Egg PC), and diunsaturated dioleoylphosphatidylcholine ( cis -and trans -DOPC). AFM nanoindentation measurements revealed that the elasticity of liposomes followed the order of trans -DOPC (most rigid) > DPPC > PC > cis -DOPC (most flexible). MD simulation-derived membrane thickness, acyl chain order parameter, and FRET-based full width at half-maxima (hw) of the probability distribution P (r) of donor–acceptor distance data correlated well with liposome mechanical properties. siRNA delivery experiments confirmed that liposome flexibility or rigidity directly influences their cellular transfection efficiency, where trans -DOPC is found to be superior to the other cis /monounsaturated/saturated systems, demonstrating that particle rigidity is key to efficient cellular uptake.