Nuclear pore complexes (NPCs) are sophisticated transporters assembled from diverse proteins termed nucleoporins (Nups). They control all nucleocytoplasmic transport and form a stringent barrier between the cytosol and the nucleus. While selective receptor-mediated transport enables translocation of macromolecules up to striking sizes approaching megadalton-scale, the upper cutoff for diffusion is at 40 kDa. Raising the cutoff is of particular importance for nuclear delivery of therapeutic nanoparticles, for example, gene and chemotherapy. In this work, we set out to present compounds capable of raising the cutoff to an extent enabling nuclear delivery of 6 kbp pDNA (150 kDa) in cultured human vascular endothelial cells. Of all tested compounds one is singled out, 1,6-hexanediol (1,6-HD). Our observations reveal that 1,6-HD facilitates nuclear delivery of pDNA in up to 10-20% of the tested cells, compared to no delivery at all in control conditions. It acts by interfering with bonds between Nups that occupy the NPC channel and confer transport selectivity. It also largely maintains cell viability even at high concentrations. We envisage that 1,6-HD may serve as a lead substance and usher in the design of potent new strategies to increase nuclear delivery of therapeutic nanoparticles.

中文翻译：

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通过干扰选择性核孔屏障促进质粒核递送。

核孔复合物 (NPC) 是由称为核孔蛋白 (Nups) 的多种蛋白质组装而成的复杂转运蛋白。它们控制所有核细胞质运输并在细胞质和细胞核之间形成严格的屏障。虽然选择性受体介导的运输能够使大分子易位到接近兆道尔顿规模的惊人尺寸，但扩散的上限为 40 kDa。提高截止值对于治疗性纳米颗粒的核递送（例如基因和化疗）特别重要。在这项工作中，我们着手提出能够将截止值提高到一定程度的化合物，从而能够在培养的人血管内皮细胞中进行 6 kbp pDNA (150 kDa) 的核递送。在所有测试的化合物中，我们选出了一种：1,6-己二醇 (1,6-HD)。我们的观察表明，1,6-HD 促进了高达 10-20% 的测试细胞中 pDNA 的核递送，而在对照条件下根本没有递送。它通过干扰占据 NPC 通道的 Nups 之间的键来发挥作用，并赋予传输选择性。即使在高浓度下，它也能很大程度上维持细胞活力。我们设想 1,6-HD 可以作为一种先导物质，并引导设计有效的新策略来增加治疗性纳米颗粒的核递送。