Tuning cellular uptake of nanoparticles via ligand density: Contribution of configurational entropy

The bioactivity of nanoparticles (NPs) crucially depends on their ability to cross biological membranes. A fundamental understanding of cell-NP interaction is hence essential to improve the performance of the NP-based biomedical applications. Although extensive studies of cellular uptake have converged upon the idea that the uptake process is mainly regulated by the elastic deformation of the cell membrane or NP, recent experimental observations indicate the ligand density as another critical factor in modulating NP uptake into cells. In this study, we propose a theoretical model of the wrapping of an elastic vesicle NP by a finite lipid membrane to depict the relevant energetic and morphological evolutions during the wrapping process driven by forming receptor-ligand bonds. In this model, the deformations of the membrane and the vesicle NP are assumed to follow the continuum Canham-Helfrich framework, whereas the change of configurational entropy of receptors is described from statistical thermodynamics. Results show that the ligand density strongly affects the binding energy and configurational entropy of free receptors, thereby altering the morphology of the vesicle-membrane system in the steady wrapping state. For the wrapping process by the finite lipid membrane, we also find that there exists optimal ligand density for the maximum wrapping degree. These predictions are consistent with relevant experimental observations reported in the literature. We have further observed that there are transitions of various wrapping phases (no wrapping, partial wrapping, and full wrapping) in terms of ligand density, membrane tension, and molecular binding energy. In particular, the ligand and receptor shortage regimes for the small and high ligand density are, respectively, identified. These results may provide guidelines for the rational design of nanocarriers for drug delivery.