Nanoparticle (NP)-mediated therapies are promising tools for the treatment of a wide range of diseases, including stroke and cancer, due to the outstanding performance they have shown for specifically targeting diseased sites. Importantly, the coupling of stiffness and shape of NPs has a significant influence on transportation via blood flow and internalization by targeted cells. Nevertheless, the underlying mechanism of this coupling effect on the endocytosis of NPs remains largely unexplored, resulting from a lack of clear measurement of stiffness for NPs in experiments, as well as the complexity of the endocytosis process. To overcome the above challenges, coarse-grained simulations, which can provide abundant nanoscale details and precise control of mechanical properties of NPs, were implemented to study the stiffness and shape dependence of the endocytosis of spherocylindrical NPs. To understand the coupling effect between shape and stiffness of NPs for membrane wrapping, coarse-grained molecular dynamics (CGMD) models with explicit bond, area, volume, and bending stiffness control were constructed for spherocylindrical NPs with identical volumes but different aspect ratios (ARs) ranging from 1.3 to 11.0. Results indicate that the endocytosis time of NPs increases as the aspect ratio increases due to both the increasing surface area and decreasing wrapping rate resulting from the decreasing contact perimeter. Moreover, soft and long NPs with AR = 11.0 exhibit wormlike wiggling in contrast to rodlike penetration of the stiff, enlarging the contact area and facilitating the endocytosis process. In addition, three types of NP fates are differentiated: full endocytosis, full endocytosis with membrane damage, and partial endocytosis with membrane damage. Among those patterns, damages/defects on the membrane can promote wrapping of NPs, although extra time is needed to close the defect after endocytosis. In summary, our results help gain a deeper understanding of the underlying mechanism of endocytosis of NPs with respect to geometry and particle stiffness, providing a useful guideline for designs of nanoparticles that can be implemented in next-generation nanoparticle-assisted therapy.

中文翻译：

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纳米颗粒的刚度与形状耦合的内吞作用机理：从棒状穿透到蠕虫状蠕动

纳米粒子（NP）介导的疗法是治疗各种疾病（包括中风和癌症）的有前途的工具，这是因为它们已显示出专门针对患病部位的出色性能。重要的是，NP的刚度和形状的耦合对通过血流的运输和靶细胞的内在化具有重要影响。尽管如此，这种耦合作用对NPs内吞作用的潜在机制仍未得到充分探索，这是由于缺乏对NPs的刚度的清晰测量，以及内吞作用过程的复杂性所致。为了克服上述挑战，可以使用粗粒度模拟来提供大量的纳米级细节并精确控制NP的机械性能，进行了研究以研究球状NP胞吞作用的刚度和形状依赖性。为了了解NPs的形状和刚度在膜包裹中的耦合效应，构建了具有明确的键，面积，体积和弯曲刚度控制的粗粒分子动力学（CGMD）模型，用于具有相同体积但长宽比不同的球形圆柱形NP ），范围从1.3到11.0。结果表明，NPs的内吞时间随着长宽比的增加而增加，这是由于表面积增加和接触周长减小导致包裹率降低所致。此外，AR = 11.0的软而长的NPs表现出蠕虫状的摆动，而僵硬的棒状穿透则增大了接触面积并促进了内吞作用。此外，区分NP命运的三种类型：完全内吞，具有膜破坏的完全内吞和具有膜破坏的部分内吞。在这些模式中，膜上的损伤/缺陷可促进NP的包裹，尽管胞吞后需要额外的时间来闭合缺陷。总而言之，我们的结果有助于更深入地了解NP的内吞作用的几何学和颗粒硬度方面的内在机制，从而为可在下一代纳米颗粒辅助疗法中实施的纳米颗粒设计提供了有用的指导。尽管胞吞后需要额外的时间来闭合缺损。总而言之，我们的结果有助于更深入地了解NP的内吞作用的几何学和颗粒硬度方面的内在机制，从而为可在下一代纳米颗粒辅助疗法中实施的纳米颗粒设计提供了有用的指导。尽管胞吞后需要额外的时间来闭合缺损。总而言之，我们的结果有助于更深入地了解NP的内吞作用的几何学和颗粒硬度方面的内在机制，从而为可在下一代纳米颗粒辅助疗法中实施的纳米颗粒设计提供了有用的指导。