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Iron deficiency is a major global public health problem despite decades of efforts with iron supplementation and fortification. The issue lies on the poor tolerability of the standard of care soluble iron salts, leading to non-compliance and ineffective correction of iron-deficiency anaemia. Iron nanoformulations have been proposed to fortify food and feed to address these issues. Since it was just postulated that some nanoparticles (NPs) might cross the plasma membrane also by a non-endocytotic pathway gaining direct access to the cytoplasm, we have studied iron NP uptake under this perspective. To this aim, we have used a recently tested protocol that has proven to be capable of following the cytoplasmic changes of iron concentration dynamics and we have demonstrated that iron oxide NPs, but not zerovalent iron NPs nor iron oxide NPs that were surrounded by a protein corona, can cross plasma membranes. By electrophysiology, we have also shown that a small and transient increase of membrane conductance parallels NP crossing of plasma membrane.

The ability of nanoparticles (NPs) to be promptly uptaken by the cells makes them both dangerous and useful to human health. It was recently postulated that some NPs might cross the plasma membrane also by a non-endocytotic pathway gaining access to the cytoplasm. To this aim, after having filled mature Xenopus oocytes with Calcein, whose fluorescence is strongly quenched by divalent metal ions, we have exposed them to different cobalt NPs quantifying quenching as evidence of the increase of the concentration of Co2+ released by the NPs that entered into the cytoplasm. We demonstrated that cobalt oxide NPs, but not cobalt nor cobalt oxide NPs that were surrounded by a protein corona, can indeed cross plasma membranes.

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