Interplay between ligand mobility and nanoparticle geometry during cellular uptake of PEGylated liposomes and bicelles

Abstract

We explore the cellular uptake process of PEGylated liposomes and bicelles by investigating their membrane wrapping process using large-scale molecular dynamics simulations. We find that due to the mobility of ligands on the liposome/bicelle, the membrane wrapping process of a PEGylated liposome/bicelle can be divided into two stages, whose transition is determined by a critical wrapping fraction f_c; it is reached when all the ligands are exhausted and bound to receptors within the cell membrane. Before this critical scenario is approached, the grafted polyethylene glycol (PEG) polymers aggregate together within the membrane–wrapped region of the liposome/bicelle, driven by ligand–receptor binding. For wrapping fractions f > f_c, membrane wrapping cannot proceed unless a compressive membrane tension is provided. By systematically varying the membrane tension and PEG molar ratio, we establish phase diagrams about wrapping states for both PEGylated liposomes and bicelles. According to these diagrams, we find that the absolute value of the compressive membrane tension required by a fully wrapped PEGylated bicelle is smaller than that of the PEGylated liposome, indicating that the PEGylated bicelle is easily internalized by cells. Further theoretical analysis reveals that compared to a liposome, the flatter surface at the top of a bicelle makes it energetically more favored beyond the critical wrapping fraction f_c. Our simulations confirm that the interplay between ligand mobility and NP geometry can significantly change the understanding about the influence of NP geometry on the membrane wrapping process. It can help us to better understand the cellular uptake process of the PEGylated liposome/bicelle and to improve the design of lipid-like NPs for drug delivery.