Membrane-curvature-mediated co-endocytosis of bystander and functional nanoparticles.

Efficient cellular uptake of nanoparticles (NPs) is necessary for the development of nanomedicine in biomedical applications. Recently, the coadministration of functionalized NPs (FNPs) was shown to stimulate the cellular uptake of nonfunctionalized NPs (termed bystander NPs, BNPs), which presents a new strategy to achieve synergistic delivery. However, a mechanistic understanding of the underlying mechanism is still lacking. In this work, the bystander uptake effect was investigated at the cell membrane level by combining the coarse-grained molecular dynamics, potential of mean force calculation and theoretical energy analysis methods. The membrane internalization efficiency of BNPs was enhanced by co-administered FNPs, and such activity depends on the affinity of both NPs to the membrane and the resultant membrane deformation. The membrane-curvature-mediated attraction and aggregation of NPs facilitated the membrane uptake of BNPs. Furthermore, quantitative suggestions were given to modulate the BNP internalization through controlling the FNP properties such as size, concentration and surface-ligand density. Our results provide insight into the molecular mechanism of the bystander uptake effect, and offer a practical guide to regulate the cellular internalization of NPs for targeted and efficient delivery to cells.