Variable Nanoparticle-Cell Adhesion Strength Regulates Cellular Uptake

In receptor-mediated endocytosis, cells exercise biochemical control over the mechanics of adhesion to engulf foreign particles, featuring a variable adhesion strength. Here we present a thermodynamic model with which we elucidate that the variable adhesion strength critically governs the cellular uptake, yielding an uptake phase diagram in the space of ligand density and particle size. We identify from the diagram an endocytosed phase with markedly high uptake, encompassed by a lower and an upper phase boundary that are set, respectively, by the enthalpic and entropic limits of the adhesion strength. The phase diagram may provide useful guidance to the rational design of nanoparticle-based therapeutic and diagnostic agents.

Figure 1

Schematic of three possible associations of NPs to the lipid membrane: suspended in solution, partially wrapped with different degrees of wrapping, and endocytosed.

Figure 2

A two-dimensional phase diagram on the ($R-{\xi }_g$) plane characterizes the interrelated effects of particle size and ligand density on the cellular uptake. The dashed and dash-dotted lines are the lower and upper transition boundaries, respectively. The dotted line represents the theoretical lower bound derived from local wrapping energetics [Eqs. (7) or (8)]. The cellular uptake in the endocytosed phase is markedly high, while those in the other two phases vanish. The color bar indicates the level of cellular uptake.

Figure 3

The effects of ligand density and particle size on the cellular uptake. All the solid lines represent the total uptake $n_K$. The dashed lines represent the corresponding uptake contributed by $n_{KL}$.