Magnetite Fe3O4 nanoparticles enhance mild microwave ablation of tumor by activating the IRE1-ASK1-JNK pathway and inducing endoplasmic reticulum stress

Purpose: With the development of nanomedicine, microwave ablation enhanced by multi-functional nanoplatforms has been widely studied for synergistic cancer therapy. Though scientists have got a lot of significant achievements in this field, the detailed molecular mechanisms and potential targets of microwave ablation enhanced by multifunctional nano-platforms still need further exploration. In this study, we found that a kind of magnetite Fe3O4 nanoparticles (Fe3O4 NPs) could induce severe endoplasmic reticulum stress and activate cancer apoptosis under the irradiation of mild microwave. Methods: In this study, plenty of studies including cell immunofluorescence, mitochondrial membrane potential, electron microscopy, atomic force microscopy and microwave ablation in vivo were conducted to explore the molecular mechanisms and potential targets of microwave ablation enhanced by the Fe3O4 NPs. Results: The IRE1-ASK1-JNK pathway was strongly activated in A375 cells treated with both Fe3O4 NPs and mild microwave. The endoplasmic reticulum of the A375 cells was significantly dilated and exhibited ballooning degeneration. By investigating the mitochon-drial membrane potential (ΔΨm), we found that the mitochondria of cancer cells had been significantly damaged under microwave treatment coupled with Fe3O4 NPs. In addition, melanoma of B16F10-bearing mice had also been effectively inhibited after being treated with Fe3O4 NPs and microwave. Conclusion: In this study, we found that a kind of magnetite Fe3O4 nanoparticles could induce severe ER stress and activate cancer apoptosis under mild microwave irradiation. Apparent apoptosis had been observed in the A375 cells under a scanning electron microscope and transmission electron microscope. Moreover, melanoma had also been inhibited effectively in vivo. As a result, the endoplasmic reticulum stress is a promising target with clinical potential in nanomedicine and cancer therapy.