(726f) Mechanism of Lipid Bilayer Insertion By Amphiphilic, Monolayer-Protected Gold Nanoparticles

Small, monolayer-protected nanoparticles (NPs) have been increasingly valuable in biological applications due to the ability to tune features of the protecting monolayer to tailor interactions with the biological milieu. Recently, a particular class of amphiphilic NPs with surface properties that mimic typical globular proteins were shown to enter cells via a non-endocytic, non-disruptive process that could be of broad interest for applications in drug or gene delivery. Here, we use detailed atomistic molecular dynamics simulations to understand the behavior of these NPs at the interface with the lipid bilayer and to gain molecular insight into the origin of these experimental observations. We find that the amphiphilic NPs insert into the bilayer to obtain a configuration resembling that of a membrane-embedded protein due to favorable interactions between hydrophobic molecules on the NP surface and the hydrophobic bilayer core. We further identify a novel kinetic pathway for insertion that mimics the early onset of vesicle-vesicle fusion. Finally, we derive design guidelines to both maximize the thermodynamic driving force for insertion and minimize kinetic barriers, enabling the creation of NPs optimized for bilayer insertion and cellular uptake. Our work thus emphasizes that carefully tuning NP surface coatings to resemble existing biological materials enables unique interactions with the cell membrane that we expect will be valuable for applications in drug delivery, bioimaging, and biosensing.