Mitochondria play a key role in oncogenesis and constitute one of the most important targets for cancer treatments. Although the most effective way to deliver drugs to mitochondria is by covalently linking them to a lipophilic cation, the in vivo delivery of free drugs still constitutes a critical bottleneck. Herein, we report the design of a mitochondria-targeted metal–organic framework (MOF) that greatly increases the efficacy of a model cancer drug, reducing the required dose to less than 1% compared to the free drug and ca. 10% compared to the nontargeted MOF. The performance of the system is evaluated using a holistic approach ranging from microscopy to transcriptomics. Super-resolution microscopy of MCF-7 cells treated with the targeted MOF system reveals important mitochondrial morphology changes that are clearly associated with cell death as soon as 30 min after incubation. Whole transcriptome analysis of cells indicates widespread changes in gene expression when treated with the MOF system, specifically in biological processes that have a profound effect on cell physiology and that are related to cell death. We show how targeting MOFs toward mitochondria represents a valuable strategy for the development of new drug delivery systems.

中文翻译：

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功能化金属有机框架系统的设计，用于增强线粒体的靶向递送

线粒体在肿瘤发生中发挥着关键作用，是癌症治疗最重要的靶点之一。尽管将药物递送至线粒体的最有效方法是将它们与亲脂性阳离子共价连接，但游离药物的体内递送仍然构成关键瓶颈。在此，我们报告了一种靶向线粒体的金属有机框架（MOF）的设计，该框架大大提高了模型癌症药物的功效，与游离药物和大约相比，将所需剂量减少至不到 1%。与非靶向 MOF 相比，降低了 10%。使用从显微镜到转录组学的整体方法来评估系统的性能。用靶向 MOF 系统处理的 MCF-7 细胞的超分辨率显微镜揭示了重要的线粒体形态变化，这些变化与孵化后 30 分钟的细胞死亡明显相关。细胞的全转录组分析表明，用 MOF 系统处理时，基因表达发生了广泛的变化，特别是在对细胞生理学产生深远影响且与细胞死亡相关的生物过程中。我们展示了如何将 MOF 靶向线粒体作为开发新药物递送系统的宝贵策略。