自组装的多价DNA纳米笼是一类新兴的分子，可用于生物医学应用。在这里，我们研究了AS1411自由适配体、AS1411连接纳米笼(Apt-NCs)和既携带叶酸又携带AS1411功能化的纳米笼(Fol-Apt-NCs)在HeLa和MDA-MB-231癌细胞系中诱导细胞毒性的分子机制。这三种处理显示出不同的细胞毒性疗效，Fol-Apt-NCs在抑制细胞增殖、诱导凋亡途径和ROS激活方面对HeLa和MDA-MB-231细胞都最有效。RNA-seq分析可用于确定各种处理方式引起的生物学功能和基因改变，取决于AS1411的细胞内入路，突显了这两种癌细胞系的不同行为。值得注意的是，Fol-Apt-NCs在MDA-MB-231细胞中改变了与癌症化疗耐药性相关的一部分基因的表达，而在HeLa细胞中未改变，这可能解释了通过DNA纳米笼输送药物的三阴性乳腺癌细胞的化疗敏感性增加。版权所有 © 2023 Elsevier Inc.

Self-assembled multivalent DNA nanocages are an emerging class of molecules useful for biomedicine applications. Here, we investigated the molecular mechanisms of cytotoxicity induced by AS1411 free aptamer, AS1411-linked nanocages (Apt-NCs) and nanocages harboring both folate and AS1411 functionalization (Fol-Apt-NCs) in HeLa and MDA-MB-231 cancer cell lines. The three treatments showed different cytotoxic efficacy and Fol-Apt-NCs resulted the most effective in inhibiting cell proliferation and inducing apoptotic pathways and ROS activation in both HeLa and MDA-MB-231 cells. RNA-seq analysis allowed to identify biological functions and genes altered by the various treatments, depending on the AS1411 route of intracellular entry, highlighting the different behavior of the two cancer cell lines. Notably, Fol-Apt-NCs altered the expression of a subset of genes associated to cancer chemoresistance in MDA-MB-231, but not in HeLa cells, and this may explain the increased chemosensitivity to drugs delivered through DNA nanocages of the triple negative breast cancer cells.Copyright © 2023. Published by Elsevier Inc.