Apoferritin-Cu(II) Nanoparticles Induce Oncosis in Multidrug-Resistant Colon Cancer Cells

Multidrug resistance (MDR) limits the application of clinical chemotherapeutic drugs. There is an urgent need to develop non-apoptosis-inducing agents that circumvent drug resistance. Herein, four therapeutic copper complexes encapsulated in natural nanocarrier apoferritin (AFt-Cu1-4) are reported. Although they are isomers, they exhibit significantly different organelle distributions and cell death mechanisms. AFt-Cu1 and AFt-Cu3 accumulate in the cytoplasm and induce autophagy, whereas AFt-Cu2 and AFt-Cu4 can quickly enter the nucleus and trigger oncosis. Excitedly, AFt-Cu2 and AFt-Cu4 show a strong tumor growth inhibition effect in mice models bearing multidrug-resistant colon xenograft via intravenous injection. To the best of the authors' knowledge, this is the first example of metal-based nucleus-targeted oncosis inducers overcoming multidrug resistance in vivo. Four Cu(II) complexes encapsulated in apoferritin are developed as therapeutic nano-agents. As isomers, Cu1 and Cu3 distribute in the cytoplasm while Cu2 and Cu4 enter the nucleus. They circumvent tumor drug resistance by inducing autophagy or oncosis. The ability of AFt-Cu2 and AFt-Cu4 to overcome multidrug resistance is demonstrated in vitro and in vivo.image