Mitochondria-targeted nanoparticles, such as liposomes, polymers and inorganic particles, suffer from heterogeneity, low biocompatibility and low drug loading efficiency. Here, we present a novel delivery platform based on tetrahedral DNA nanostructures (TDNs) that enable the mitochondrial transportation of the anticancer drug doxorubicin (DOX) for cancer therapy. In our design, DOX was intercalated into TDNs, which executed the cell-killing function inside the tumor cells. Various numbers of D-(KLAKLAK)₂ (KLA) were conjugated to TDNs to achieve the mitochondria targeting effect. The mean size of the KLA-modified TDNs was about 15 nm, and the TDNs were stable in FBS. The DOX loading efficiency of the TDNs was up to around 77%. The 3KLA-modified TDNs exhibited the most efficient DOX accumulation in mitochondria, leading to an effective release of cytochrome c, and the upregulated expression levels of caspase-9, caspase-3, p21 and p53. Meanwhile, 3KLA-TDNs/DOX elevated the pro-apoptotic Bax, reduced the anti-apoptotic Bcl-2 protein expression and increased the Bax/Bcl-2 ratio, which finally activated the mitochondria-mediated, programmed apoptosis pathway to enhance the anticancer efficacy in vitro. This 3KLA-TDN and DOX co-assembling strategy can be further developed to transport other anthracyclines and chemotherapeutic agents for enhanced apoptosis effects.

中文翻译：

---

线粒体靶向的四面体DNA纳米结构用于阿霉素的传递和细胞凋亡的增强。

线粒体靶向的纳米颗粒，例如脂质体，聚合物和无机颗粒，具有异质性，生物相容性低和药物装载效率低的缺点。在这里，我们介绍了一种基于四面体DNA纳米结构（TDNs）的新型递送平台，该平台可实现线粒体运输抗癌药阿霉素（DOX）进行癌症治疗。在我们的设计中，将DOX插入TDN中，该TDN在肿瘤细胞内部执行细胞杀伤功能。各种数量的D-（KLAKLAK）₂（KLA）与TDN偶联以实现线粒体靶向作用。KLA修饰的TDN的平均大小约为15 nm，并且TDN在FBS中稳定。TDN的DOX加载效率高达77％左右。3KLA修饰的TDN在线粒体中表现出最有效的DOX积累，从而导致细胞色素c的有效释放以及caspase-9，caspase-3，p21和p53的表达水平上调。同时，3KLA-TDNs / DOX升高了促凋亡的Bax，降低了抗凋亡的Bcl-2蛋白表达并提高了Bax / Bcl-2的比例，最终激活了线粒体介导的程序性凋亡途径，从而增强了抗癌功效体外。 可以进一步开发这种3KLA-TDN和DOX协同组装策略，以转运其他蒽环类药物和化学治疗剂，以增强细胞凋亡作用。