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Title: Biotransformation modulates the penetration of metallic nanomaterials across an artificial blood–brain barrier model

Abstract: Although the brain is protected by a tight physiological guardian named the blood–brain barrier (BBB), deposition of engineered nanomaterials (ENMs) in the brain and consequent neurotoxicity has been reported. To date, it is still unclear whether and how ENMs enter the brain by crossing the BBB. In this study, we found that metallic ENMs transform in the BBB as affected by their shape, size, and intrinsic solubility, which in turn modulates their transport form, efficiency, and pathways through the BBB and, consequently, their neurotoxicity. The library of quantitative data on the chemical transformations presented here will support in silico modeling and prediction of the neurotoxicity of NMs and facilitate the tailored design of safe NMs.