Nanoparticle transport across model cellular membranes: when do solubility-diffusion models break down?

The interactions of nanoparticles (NPs) with cellular membranes and subsequent transport processes have major implications for the biology, toxicology, and pharmacology of nanoscale materials. Moreover, understanding and predicting the behaviors of diverse NP designs in a physiological setting is of increasing technological and regulatory importance. Still, the current complexity of experiments and lack of a consensus in modeling and simulation preclude a clear picture of relevant NP-membrane interaction modes and mechanisms, particularly for particles on the similar to 1-10 nm scale. Here, we leverage detailed coarse-grained molecular dynamics simulations with advanced sampling strategies to uncover the thermodynamic driving forces and possible kinetic pathways of approximately 0.5-2.0nm hydrophilic, hydrophobic, and 'interfacially active' particles with model lipid bilayer membranes. Using the simulations, we test the applicability of well-established theoretical models for the permeability of small molecule transport-Overton's rule and the inhomogeneous solubility-diffusion model-and conclude that the former is overly-simplified for fluctuating lipid bilayers, while the latter breaks down at the larger particle sizes due to the influence of other physics like membrane undulations. We place this work in the context of recent simulation studies, and conclude with critical physical and methodological insights to guide future thermodynamic and kinetic studies of NP-membrane interactions.