Cell entry of anionic nano-objects has been observed in various types of viruses and self-assembled DNA nanostructures. Nevertheless, the physical mechanism underlying the internalization of these anionic particles across the negatively charged cell membrane remains poorly understood. Here, we report the use of virus-mimicking designer DNA nanostructures with near-atomic resolution to program “like-charge attraction” at the interface of cytoplasmic membranes. Single-particle tracking shows that cellular internalization of tetrahedral DNA nanostructures (TDNs) depends primarily on the lipid-raft-mediated pathway, where caveolin plays a key role in providing the short-range attraction at the membrane interface. Both simulation and experimental data establish that TDNs approach the membrane primarily with their corners to minimize electrostatic repulsion, and that they induce uneven charge redistribution in the membrane under the short-distance confinement by caveolin. We expect that the nanoscale like-charge attraction mechanism provides new clues for viral entry and general rules for rational design of anionic carriers for therapeutics.

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细胞膜界面上的DNA纳米结构编程的电荷吸引

阴离子纳米物体的细胞进入已在各种类型的病毒和自组装DNA纳米结构中观察到。然而，对这些阴离子颗粒在带负电的细胞膜上的内在化作用的物理机制仍然知之甚少。在这里，我们报道了使用具有近似原子分辨率的模仿病毒的设计器DNA纳米结构来对细胞质膜界面上的“类似电荷吸引”进行编程。单粒子跟踪表明，四面体DNA纳米结构（TDN）的细胞内在化主要取决于脂质-筏介导的途径，其中小窝蛋白在膜界面的短程吸引中起关键作用。模拟和实验数据均确定，TDNs主要通过其角部接近膜以最小化静电排斥，并且它们在由小孔蛋白短距离限制的情况下在膜中引起不均匀的电荷重新分布。我们期望纳米级的电荷吸引机制为病毒进入提供新的线索，并为治疗用阴离子载体的合理设计提供一般规则。