Safety-by-Design of Metal Oxide Nanoparticles Based on the Regulation of their Energy Edges.

The safety of metal oxide (MOx) nanoparticles (NPs) has been highly concerned because of their wide application and potential toxicological injury. The safe-by-design strategy is usually developed to make safer MOx NPs based on regulation of their physicochemical properties. In the present study, manganese oxide (Mn3 O4 ) NPs, as a representative of insoluble toxic MOx NPs, are doped with a series of transition metal to regulate their conduction band energy (Ec ) out of biological redox potential range (BRPR) or Fermi energy (Ef ) far away from valence band energy (Ev ), aiming at completely eliminating the toxicity or significantly reducing the toxicity. It is found that all these M-doping cannot move Ec of Mn3 O4 NPs out of the BRPR but zinc (Zn)-, copper (Cu)-, and chromium (Cr)-doping do move Ef far away from Ev , where Zn-doping results in the largest |Ef - Ev | value. Various abiotic, in vitro and in vivo assessments reveal that Zn-, Cu-, and Cr-doped Mn3 O4 NPs can generate lower amount of *OH and trigger weaker injury than Mn3 O4 NPs, where Zn-doped Mn3 O4 NPs show the lowest toxicity. Regulating Ef far away from Ev becomes a feasible safe-by-design approach to achieve safe MOx NPs.