Liang Junshi, Chen Pengyu, Dong Bojun, Huang Zihan, Zhao Kongyin, Yan Li-Tang
Key Laboratory of Advanced Materials (MOE), Department of Chemical Engineering, Tsinghua University , Beijing 100084, P. R. China.
State Key Laboratory of Separation Membranes and Membrane Processes, Tianjin Polytechnic University , Tianjin 300387, China.
Biomacromolecules. 2016 May 9;17(5):1834-44. doi: 10.1021/acs.biomac.6b00241. Epub 2016 Apr 13.
Nearly all nanomedical applications of dendrimer-like soft nanoparticles rely on the functionality of attached ligands. Understanding how the ligands interact with the receptors in cell membrane and its further effect on the cellular uptake of dendrimer-like soft nanoparticles is thereby a key issue for their better application in nanomedicine. However, the essential mechanism and detailed kinetics for the ligand-receptor interaction-mediated transmembrane transport of such unconventional nanoparticles remain poorly elucidated. Here, using coarse-grained simulations, we present the very first study of molecular mechanism and kinetics behaviors for the transmembrane transport of dendrimer-like soft nanoparticles conjugated with ligands. A phase diagram of interaction states is constructed through examining ligand densities and membrane tensions that allows us to identify novel endocytosis mechanisms featured by the direct wrapping and the penetration-extraction vesiculation. The results provide an in-depth insight into the diffusivity of receptors and dendrimer in the membrane plane and demonstrate how the ligand density influences receptor diffusion and uptake kinetics. It is interesting to find that the ligand-conjugated dendrimers present superdiffusive behaviors on a membrane, which is revealed to be driven by the random fluctuation dynamics of the membrane. The findings facilitate our understanding of some recent experimental observations and could establish fundamental principles for the future development of such important nanomaterials for widespread nanomedical applications.
几乎所有类树枝状软纳米颗粒的纳米医学应用都依赖于附着配体的功能。因此，了解配体如何与细胞膜中的受体相互作用及其对类树枝状软纳米颗粒细胞摄取的进一步影响，是它们在纳米医学中更好应用的关键问题。然而，这种非常规纳米颗粒的配体-受体相互作用介导的跨膜转运的基本机制和详细动力学仍未得到充分阐明。在这里，我们使用粗粒度模拟，首次对与配体共轭的类树枝状软纳米颗粒的跨膜转运的分子机制和动力学行为进行了研究。通过检查配体密度和膜张力构建了相互作用状态的相图，这使我们能够识别以直接包裹和穿透-提取囊泡形成为特征的新型内吞机制。结果深入洞察了受体和树枝状聚合物在膜平面中的扩散率，并展示了配体密度如何影响受体扩散和摄取动力学。有趣的是，发现配体共轭的树枝状聚合物在膜上呈现超扩散行为，这被揭示是由膜的随机涨落动力学驱动的。这些发现有助于我们理解最近的一些实验观察结果，并可为这类重要纳米材料在广泛的纳米医学应用中的未来发展建立基本原理。
