Stochastic modeling of nanoparticle internalization and expulsion through receptor-mediated transcytosis

Receptor-mediated transcytosis (RMT) is a fundamental mechanism for the transcellular transport of nanoparticles. RMT is a complex process, during which the nanoparticles actively interact with the membrane and the membrane profile undergoes extreme deformations for particle internalization and expulsion. In this work, we developed a stochastic model to study the endocytosis and exocytosis of nanoparticles across soft membranes. The model is based on the combination of a stochastic particle binding model with a membrane model, and accounts for both clathrin-mediated endocytosis for internalization and actin-mediated exocytosis for expulsion. Our results showed that nanoparticles must have certain avidity with enough ligand density and ligand-receptor binding affinity to be taken up, while too high avidity limited the particle release from the cell surface. We further explored the functional roles of actin during exocytosis, which has been a topic under active debate. Our simulations indicated that the membrane compression due to the actin induced tension tended to break the ligand-receptor bonds and to shrink the fusion pore. Therefore, an intermediate tension promoted the fusion pore expansion and nanoparticle release, while high tension prohibits particle release. Our model provides new and critical mechanistic insights into RMT, and represents a powerful platform for aiding the rational design of nanocarriers for controlled drug delivery.