Cancer metastasis, which increases the mortality in a short period of time, has been considered as the main challenge in tumor treatment. However, tumor growth suppression also should not be ignored in cancer metastasis treatment. Recently, accumulating evidences have suggested that mitochondria play an important role in mitigating caner metastasis. Nucleus, as the repository of genetic information, plays a key role in cell proliferation. However, it remains elusive that the concurrent impairment of nucleus and mitochondria may achieve better anti-tumor and anti-metastatic effects. Here, we designed a mitochondria-penetrating peptide modified doxorubicin (MPP-Dox) loaded N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer conjugates (PM), as well as a nuclear accumulating HPMA copolymer Dox conjugates (PN) by the nuclear tendency of Dox. After co-delivering the two copolymers (abbreviation for PMN), PM promoted cell apoptosis and inhibited tumor metastasis by damaging mitochondria, whereas PN suppressed cell proliferation and promoted apoptosis by destroying nucleus. Importantly, PM and PN complemented each other as expected. The mitochondrial dysfunction and tumor metastasis inhibition of PM was improved by PN, while cell proliferation suppression and apoptosis by nucleus destroying of PN was enhanced by PM. As a result, tumor growth of breast cancer 4T1 cells in vivo was significantly restrained and lung metastasis was potently decreased and almost eradicated, fully reflecting the advantages of organelle targeting combination therapy. As a consequence, our work showed that concurrent impairment of nucleus and mitochondria was feasible and beneficial to metastatic cancer treatment.

在短时间内增加死亡率的癌症转移被认为是肿瘤治疗的主要挑战。然而，在癌症转移治疗中也不应忽视肿瘤生长抑制。最近，越来越多的证据表明线粒体在减轻癌症转移方面发挥着重要作用。细胞核作为遗传信息的储存库，在细胞增殖中起着关键作用。然而，细胞核和线粒体的同时受损可能会达到更好的抗肿瘤和抗转移作用仍然难以捉摸。在这里，我们设计了一种线粒体穿透肽修饰的阿霉素（MPP-Dox）负载N-(2-羟丙基)甲基丙烯酰胺 (HPMA) 共聚物共轭物 (PM)，以及通过 Dox 的核趋势积累的 HPMA 共聚物 Dox 共轭物 (PN)。共递送两种共聚物（PMN的缩写）后，PM通过破坏线粒体促进细胞凋亡并抑制肿瘤转移，而PN通过破坏细胞核抑制细胞增殖并促进细胞凋亡。重要的是，PM 和 PN 按预期相互补充。PN改善了PM的线粒体功能障碍和肿瘤转移抑制，而PN破坏细胞核导致的细胞增殖抑制和凋亡被PM增强。结果，体内乳腺癌4T1细胞的肿瘤生长显着抑制肺转移，有效减少和几乎根除肺转移，充分体现了细胞器靶向联合治疗的优势。因此，我们的工作表明，细胞核和线粒体的同时损伤是可行的，并且有利于转移性癌症的治疗。