The valence state of iron-based nanomaterials determines the ferroptosis potential in a zebrafish model.

Many nanomaterials containing different valences of iron have been designed for applications in biomedicine, energy, catalyzers, nanoenzymes, and so on. However, the toxic effects of the valence state of iron in iron-based nanomaterials are still unclear. Here, three different-valence iron-based nanomaterials (nFe@Fe3O4, nFe3O4 and nFe2O3) were synthesized and exposed to zebrafish embryos and mammalian cardiomyocytes. All of them induced ferroptosis along with an increase in valence through iron overload and the Fenton reaction. Specifically, we exposed Tg (cmlc2:EGFP) zebrafish to the three iron-based nanomaterials and found that nFe@Fe3O4 treatments led to enlarged ventricles, while nFe3O4 and nFe2O3 increased atrial size, which was consistent with the results from hematoxylin-eosin staining and in situ hybridization. Moreover, we used ferroptosis inhibitors (ferrostatin-1 or deferoxamine) to treat zebrafish along with nanoparticles exposure and found that the cardiac developmental defects caused by nFe3O4 and nFe2O3, but not nFe@Fe3O4, could be completely rescued by ferroptosis inhibitors. We further found that nFe@Fe3O4, rather than nFe3O4 and nFe2O3, reduced the dissolved oxygen in the medium, which resulted in hypoxia and acceleration of heart tube formation and ventricular enlargement, and both were fully rescued by oxygen donors combined with ferroptosis inhibitors. Consistently, these findings were also observed in mammalian cardiomyocytes. In summary, our study demonstrates that the valence state of iron-based nanomaterials determines the ferroptosis potential. Our study also clarifies that high-valence iron-based nanomaterials induce an enlarged atrium via ferroptosis, while low-valence ones increase the ventricular size through both hypoxia and ferroptosis, which is helpful to understand the potential adverse effects of different valences of iron-based nanomaterials on environmental health and assure the responsible and sustainable development of nanotechnology.

Porous yolk-shell Fe/Fe3O4 nanoparticles with controlled exposure of highly active Fe(0) for cancer therapy.

The iron-based Fenton-type reaction has drawn tremendous attention in cancer therapy. Compared with oxidized iron, Fe(0) possesses high catalytic activity but unstable for biomedical application. Here, we report a new strategy to stabilize Fe(0) via a porous yolk shell nanostructure of Fe/Fe3O4 (PYSNPs) in normal physiological condition, and to control the release of Fe(0) in tumor microenvironment for enhanced cancer therapy. These PYSNPs display superior tumor inhibition with the IC50 down to 20 µg/mL (over 1 mg/mL for iron oxide nanoparticles as control) for HepG2 cell. A single intravenous injection of as low as 1 mg/kg dosage is effective to suppress tumor growth in vivo. Moreover, the disintegration of PYSNPs in the acidic tumor microenvironment could cause significant change in MRI signal for contrast-enhanced diagnosis. Of note, the resulting Fe3O4 fragments are renal clearable with minimized side effect. In all, this work represented a nanoplatform to stabilize and selectively deliver Fe(0) for highly effective cancer therapy.