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To understand the potential cytotoxicity of perfluoroalkyl substances (PFAS), we study their interactions with a model phospholipid bilayer membrane using molecular dynamics (MD) simulations. Four typical PFAS molecules are investigated, including perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorooctanesulfonic acid (PFOS), and perfluorohexane sulfonate (PFHxS). All of these PFAS molecules are found to spontaneously penetrate the lipid bilayer within a short simulation time (a few nanoseconds). During the penetration process, further free-energy analysis reveals that a PFAS molecule encounters an energy barrier at the bilayer/water interface. To overcome this free-energy barrier, the PFAS molecule flips itself at the interface. We further investigate the influence of embedded PFAS molecules on the membrane properties. All of the embedded PFAS molecules are found to produce a cholesterol-like condensing effect on the lipid bilayer, which includes increases of the order parameters of lipid tails and the thickness of the lipid bilayer and a decrease of area per lipid. Moreover, the PFAS molecules are found to form hydrogen bonds with oxygen atoms at three different positions of a lipid molecule. Our work reveals the penetration pathway of PFAS molecules entering into a lipid bilayer. In addition, the cholesterol-like condensing effect induced by embedded PFAS molecules on model membranes is systematically investigated and discussed. Our simulations can help understand the physical mechanisms of PFAS cytotoxicity.

Using coarse-grained molecular dynamics simulations, we systematically investigate the receptor-mediated endocytosis of elastic nanoparticles (NPs) with different sizes, ranging from 25 to 100 nm, and shapes, including sphere-like, oblate-like, and prolate-like. Simulation results provide clear evidence that the membrane wrapping efficiency of NPs during endocytosis is a result of competition between receptor diffusion kinetics and thermodynamic driving force. The receptor diffusion kinetics refer to the kinetics of receptor recruitment that are affected by the contact edge length between the NP and membrane. The thermodynamic driving force represents the amount of required free energy to drive NPs into a cell. Under the volume constraint of elastic NPs, the soft spherical NPs are found to have similar contact edge lengths to rigid ones and to less efficiently be fully wrapped due to their elastic deformation. Moreover, the difference in wrapping efficiency between soft and rigid spherical NPs increases with their sizes, due to the increment of their elastic energy change. Furthermore, because of its prominent large contact edge length, the oblate ellipsoid is found to be the least sensitive geometry to the variation in NP's elasticity among the spherical, prolate, and oblate shapes during the membrane wrapping. In addition, simulation results indicate that conflicting experimental observations on the efficiency of cellular uptake of elastic NPs could be caused by their different mechanical properties. Our simulations provide a detailed mechanistic understanding about the influence of NPs' size, shape, and elasticity on their membrane wrapping efficiency, which serves as a rational guidance for the design of NP-based drug carriers.

Nanomaterials have been widely used in the design of drug delivery platforms. This work computationally explores the vascular dynamics of nanoworms as drug carriers within blood flow by considering the effects of nanoworm length, stiffness, and local physiological conditions such as hematocrit. We found that nanoworms with length of 8 μm and moderate stiffness are the optimal choice as drug carriers for circulating within normal vascular network due to their lower near wall margination. Compared to those of spherical rigid particles, these nanoworms demonstrate significant demargination behaviors at hematocrit 20%, induced by the local hydrodynamic interactions. Specifically, the interactions between nanoworms and red blood cells create asymmetrical local flow fields, resulting in the demargination of nanoworms. In addition, the flexibility of nanoworms enables them to conform to the deformed shape of red blood cells under shear flow, leading to their high concentration within the core region of vessels. Therefore, the long blood circulation time of nanoworms can be partially attributed to their demargination behaviors and intertwinement with red blood cells. According to these simulation results, tuning the length and stiffness of nanoworms is the key to design drug carries with reduced near wall margination within normal vascular networks and extend their blood circulation time.