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 (Mn O ) NPs, as a representative of insoluble toxic MOx NPs, are doped with a series of transition metal to regulate their conduction band energy (E ) out of biological redox potential range (BRPR) or Fermi energy (E ) far away from valence band energy (E ), aiming at completely eliminating the toxicity or significantly reducing the toxicity. It is found that all these M-doping cannot move E of Mn O NPs out of the BRPR but zinc (Zn)-, copper (Cu)-, and chromium (Cr)-doping do move E far away from E , where Zn-doping results in the largest |E - E | value. Various abiotic, in vitro and in vivo assessments reveal that Zn-, Cu-, and Cr-doped Mn O NPs can generate lower amount of •OH and trigger weaker injury than Mn O NPs, where Zn-doped Mn O NPs show the lowest toxicity. Regulating E far away from E becomes a feasible safe-by-design approach to achieve safe MOx NPs.
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