Nature of bilayer lipids affects membranes deformation and pore resealing during nanoparticle penetration

Highlights: • Membrane crossing of polyethylenimine/siRNA nanoparticles was simulated. • Different membrane lipids could lead to differences in pore formation. • Various levels of pore-mediated lipid flip-flops were observed during pore closure. • Dilauroylphosphatidylcholine membrane showed the largest number of lipid flip-flops. • Introduction of linoleic acid onto the polyethylenimine facilitate pore formation. Interactions of nanoparticles (NPs) with lipid membranes have enormous biological implications especially for gene delivery applications. In this work, using all-atom steered- and molecular dynamics simulations, we investigated deformation of lipid membranes and pore closure during a NP penetration process. Three membrane bilayer models built from 2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine (POPC), dipalmitoylphosphatidylcholine (DPPC) and dilauroylphosphatidylcholine (DLPC), and a NP formed by 2 short interfering RNA (siRNA) and 6 polyethylenimine (PEI) molecules were used. Our results showed that different membrane lipids could lead to differences in pore formation (symmetric vs. asymmetric), and could undergo different levels of pore-mediated flip-flops during the closure. DLPC showed the largest number of flip-flops among the three lipid membranes. In addition, introduction of hydrophobic linoleic acid (LA) substitution onto the PEIs was found to facilitate pore formation, since the long LA tails could insert themselves into the hydrophobic region of the membrane where the lipid tails were less aligned. Compared with DPPC, POPC and DLPC membranes had less alignment of lipid tails in the bilayer, which promoted the insertion of LA tails and hence NP entry into the cell. Our observations provide valuable insight into the membrane deformations and pore dynamics during NP penetration and will be important for the design of NP carriers for effective gene delivery.