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For nanoparticle (NP)-based drug delivery platforms, the elasticity of the NPs has a significant influence on their blood circulation time and cellular uptake efficiency. However, due to the complexity of the endocytosis process and the inconsistency in the definition of elasticity for NPs in experiments, the understanding about the receptor-mediated endocytosis process of elastic NPs is still limited. In this work, we developed a coarse-grained molecular dynamics (CGMD) model for elastic NPs. The energy change of the elastic NPs can be precisely controlled by the bond, area, volume and bending potentials of this CGMD model. To represent liposomes with different elasticities, we systematically varied the bending rigidity of elastic NPs in CGMD simulations. Additionally, we changed the radius of the elastic NPs to explore the potential size effect. Through virtual nano-indentation tests, we found that the effective stiffness of elastic NPs was determined by their bending rigidity and size. Afterwards, we investigated the receptor-mediated endocytosis process of elastic NPs with different sizes and bending rigidities. We found that the membrane wrapping of soft NPs was faster than that of the stiff ones at the early stage, due to the NP deformation induced large contact area between the NPs and the membrane. However, because of the large energy penalties induced by the NP deformation, the membrane wrapping speed of soft NPs slows down during the late stage. Eventually, the soft NPs are wrapped less efficiently than the stiff ones during the membrane wrapping process. Through systematic CGMD simulations, we found a scaling law between the cellular uptake efficiency and the phenomenal bending rigidity of elastic NPs, which agrees reasonably well with experimental observations. Furthermore, we observed that the membrane wrapping efficiencies of soft and stiff NPs with large sizes were close to each other, due to the stronger ligand–receptor binding force and smaller difference in the stiffness of elastic NPs. Our computational model provides an effective tool to investigate the receptor-mediated endocytosis of elastic NPs with well controlled mechanical properties. This study can also be applied to guide the design of NP-based drug carriers with high efficacy, by utilizing their elastic properties. [ABSTRACT FROM AUTHOR]

A core–polyethylene glycol–lipid shell (CPLS) nanoparticle consists of an inorganic core coated with polyethylene glycol (PEG) polymers, surrounded by a lipid bilayer shell. It can be self-assembled from a PEGylated core with surface-tethered PEG chains, where all the distal ends are covalently bonded to lipid molecules. Upon adding free lipids, a complete lipid bilayer shell can be formed on the surface driven by the hydrophobic nature of lipid tails, leading to the formation of a CPLS nanoparticle. The stability of CPLS nanoparticles in shear flow has been systematically studied through large scale dissipative particle dynamics simulations. CPLS nanoparticles demonstrate higher stability and less deformation in shear flow, compared with lipid vesicles. Burst leakage of drug molecules inside lipid vesicles and CPLS NPs can be induced by the large pores at their tips. These pores are initiated by the maximum stress in the waist region. It further grows along with the tank-treading motion of vesicles or CPLS NPs in shear flow. However, due to the constraints applied by PEG polymers, CPLS NPs are less deformed than vesicles with comparable size under the same flow conditions. Thus, the less deformed CPLS NPs express a smaller maximum stress at waists, demonstrating higher stability. Pore formation at waists, evolving into large pores on vesicles, leads to the burst leakage of drug molecules and complete rupture of vesicles. In contrast, although similar drug leakage in CPLS nanoparticles can occur at high shear rates, pores initiated at moderate shear rates tend to be short-lived and close due to the constraints mediated by PEG polymers. This kind of ‘self-healing’ capability can be observed over a wide range of shear rates for CPLS nanoparticles. Our results suggest self-assembled CPLS nanoparticles to exhibit high stability during blood circulation without rapid drug leakage. These features make CPLS nanoparticles candidates for a promising drug delivery platform. [ABSTRACT FROM AUTHOR]