Uncovering the Importance of Ligand Mobility on Cellular Uptake of Nanoparticles: Insights from Experimental, Computational, and Theoretical Investigations

Abstract

The cellular uptake of nanoparticles (NPs) by biological cells is an important and fundamental process in drug delivery. Previous studies reveal that the physicochemical properties of nanoparticles as well as those of functionalized ligands can both critically affect the uptake behaviors. However, the effect of the conjugation strategy (i.e., the "bond" between the ligand and the NP) on the cellular uptake is overlooked and remains largely elusive. Here, by taking the broadly employed gold nanoparticle as an example, we comprehensively assessed the relationship between the conjugation strategy and uptake behaviors by introducing three ligands with the same functional terminal but different anchoring sites. As revealed by in vitro cell experiments and multiscale molecular simulations, the uptake efficiency of gold NPs was positively correlated with the strength of the "bond" and more specifically the ligand mobility on the NP surface. Moreover, we validated the results presented above by proposing a thermodynamic theory for the wrapping of NPs with mobile ligands. Further, we also showed that the endocytic pathway of NPs was highly dependent on ligand mobility. Overall, this study uncovered a vital role of conjugation strategy in the cellular uptake and may provide useful guidelines for tailoring the biobehaviors of nanoparticles.

Unveiling Interactions of Tumor-Targeting Nanoparticles with Lipid Bilayers Using a Titratable Martini Model

“…Besides experimental investigations, molecular simulation has become a valuable tool to reveal the microscopic mechanism and improve the efficiency of the targeted drug delivery using NPs coated with various kinds of ligands. − Using dissipative particle dynamics (DPD), molecular dynamics (MD), and density functional theory (DFT) methods, several types of drug-loaded pH-responsive NPs were investigated. These pH-responsive NPs maintain well-defined amphiphilic structures at physiological conditions (pH ∼ 7.4), while becoming more flexible or disintegrating and exhibiting different interactions with lipid bilayers in acidic environments (pH 5.0–6.5) because of surface charge conversion of pH-sensitive groups induced by protonation. − In previous simulations, the methods were basically based on conventional MD or DPD simulations; i.e., the effect of the pH-sensitivity of the NPs is characterized by the interactions between the (coarse-grained) atoms in environments with estimates of protonation states based on set pH values, without explicitly taking into account the changes in protonation state depending on the local environment, as observed in experimental systems.…”

Effect of Nanoparticle Curvature on Its Interaction with Serum Proteins

“…With the rapid development of nanotechnology, the utilization of nanoparticles (NPs) as pharmaceutical carriers in biomedicine is increasingly expanding. − Upon introduction of NPs to the blood, the surrounding plasma proteins can quickly adsorb onto the surfaces of NPs, forming a protein corona (PC), which significantly affects the physicochemical properties of the NPs and their subsequent biological behaviors. − Therefore, comprehensive investigations of the characteristics and impact of the PC on NP surfaces are crucial for regulating their fate in vivo, which requires a deep understanding of the interactions between NPs and serum proteins.…”