线粒体钾离子通道已成为癌症治疗的有希望的靶点。然而，在恶性肿瘤中，其表达低或受抑制性调节，通常导致不良的癌症治疗，甚至诱导耐药性。在本文中，我们开发了一种原位线粒体靶向的人工K+通道构建策略，旨在通过破坏线粒体离子平衡来触发癌细胞凋亡。通过考虑癌细胞膜电位低于正常细胞的事实，我们的策略可以通过使用线粒体靶向的三苯基膦修饰的嵌段聚合物（MPTPP）作为载体，有选择性地将人工K+通道分子5F8运送至癌细胞的线粒体中。更重要的是，5F8可以通过嵌王冠醚在线粒体膜上定向组装而进一步形成具有K+选择性的离子通道，从而引起线粒体内K+流入和离子平衡的破坏。得益于这种设计，线粒体功能障碍，包括线粒体膜电位降低、ATP合成减少、抗凋亡蛋白BCL-2和MCL-1水平下调以及ROS水平增高，可以进一步有效地诱导多药耐药癌细胞的程序性凋亡，无论是泵依赖的耐药性还是非泵依赖的耐药性。简而言之，这种线粒体靶向的人工K+选择性离子通道构建策略可能有助于潜在的耐药性癌症治疗。本文受版权保护。保留所有权利。本文受版权保护。保留所有权利。

Mitochondrial potassium ion channels have become a promising target for cancer therapy. However, in malignant tumours, their low expression or inhibitory regulation typically leads to undesired cancer therapy, or even induces drug resistance. Herein, we developed an in situ mitochondria-targeted artificial K+ channel construction strategy, with the purpose to trigger cancer cell apoptosis by impairing mitochondrial ion homeostasis. By considering the fact that cancer cells have a lower membrane potential than that of normal cells, our strategy could selectively deliver artificial K+ channel molecule 5F8 to the mitochondria of cancer cells, by using a mitochondria-targeting triphenylphosphine modified block polymer (MPTPP) as a carrier. More importantly, 5F8 could further specifically form a K+ -selective ion channel through the directional assembly of crown ethers on the mitochondrial membrane, thereby inducing mitochondrial K+ influx and disrupting ions homeostasis. Thanks to this design, mitochondrial dysfunction, including decreased mitochondrial membrane potential, reduced ATP synthesis, downregulated anti-apoptotic BCL-2 and MCL-1 protein levels, and increased ROS levels, could further effectively induce the programmed apoptosis of multidrug-resistant cancer cells, no matter in case of pump or non-pump dependent drug resistance. In short, this mitochondria-targeted artificial K+ -selective ion channel construction strategy might be beneficial for potential drug resistance cancer therapy. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.