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

Abstract 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.