Theoretical Investigation Of Nanoparticle Cellular Endocytosis Using Molecular Dynamics Simulations

Membrane is the basic part of cell and it is a bilayer made up of phospholipids by the hydrophobic interaction in the solution.Nanoparticle(NP)is a promising platform in clinical diagnostics and therapeutics.Understanding the interaction of nanoparticles(NP)with cell membrane,ard regulating its cellular uptake processes are of funda-mental importance to the design of drug delivery system with minimum toxicity,high efficiency and long circulation time.In the first part,the procedure of coarse-graining combined with free energy cal-culations,we studied the endocytic process for spherical,prolate and oblate particles with varied aspect ratios,volume and interaction strengths.Rich dynamic wrapping be-haviors have been observed.Small ellipsoids follow a pathway that includes particles laying-down,membrane invagination wrapping,and then disruption of the membrane neck.However,the step of particle laying-down is skipped for large ellipsoids.Because of the significantly decreased local mean curvature at the side edge(oblate ellipsoid)or tips(prolate ellipsoid),the rotation is less favorable for particles with large volume.Given the existence of a local minimum and an energy barrier during the endocytic process presented by our free energy calculations,the oblate particle provides longer endocytic time than the corresponding prolate particle.For large particles,the free en-ergy surfaces are smooth,with no local minimum.When we increase the interaction strength between the membranes and the particles,the endocytic process is greatly af-fected.Moreover,a sandwiched structure,in which the particle lays between the two membrane layers,was observed for both prolate and oblate particles.In the second part,we built an elastically deformable NP model with tunable mor-phological and mechanical properties.Our computational results suggest that the cellu-lar uptake of deformable NPs depending on their shape:the increase of particle softness significantly slows down the uptake rate for spherical NP,slightly retards for prolate NP,whereas promotes the uptake of oblate NP.The intrinsic mechanisms have been carefully investigated through the analysis of endocytic mechanism and free energy cal-culations.These findings provide unique insights into how deformable NP penetrates across a cell membrane,and offer novel possibilities for designing effective NP-based carriers for drug deliver.In the last part,we studied the cooperative endocytic process of two elastic NPs by the membrane of varied rigidity.Rich states and endocytic pathways are observed from our computational results.In a word,the prolate NPs are uptaken by membrane with the laststate of head to head,however,the oblate NPs are uptaken with the laststate of shoulder by shoulderin the cooperative process.For the spherical NPs,distinguished laststate are presented for soft and rigid membrane.When wrapped by soft bilayer membrane,the two spheres are coated by bilayer into two microvesicles,and these two microvesicles keeps in touch at last.For the case of rigid membrane,the two bare spheres are keeps in touch during the endocytic event,and achieves the endocytosis as a whole.In conclusion,the NPs are uptaken in a cooperative mechanism.During the endocytosis,the NPs are favorable to contact with each other to achieve a less area with larger mean curvature.