Intracerebral injection of graphene oxide nanosheets mitigates microglial activation without inducing acute neurotoxicity: A pilot comparison to other nanomaterials

Carbon‐based nanomaterials (CNMs) are being explored for neurological applications. However, systematic in vivo studies investigating the effects of CNM nanocarriers in the brain and how brain cells respond to such nanomaterials are scarce. To address this, functionalized multiwalled carbon nanotubes and graphene oxide (GO) sheets are injected in mice brain and compared with charged liposomes. The induction of acute neuroinflammatory and neurotoxic effects locally and in brain structures distant from the injection site are assessed up to 1 week postadministration. While significant neuronal cell loss and sustained microglial cell activation are observed after injection of cationic liposomes, none of the tested CNMs induces either neurodegeneration or microglial activation. Among the candidate nanocarriers tested, GO sheets appear to elicit the least deleterious neuroinflammatory profile. At molecular level, GO induces moderate activation of proinflammatory markers compared to vehicle control. At histological level, brain response to GO is lower than after vehicle control injection, suggesting some capacity for GO to reduce the impact of stereotactic injection on brain. While these findings are encouraging and valuable in the selection and design of nanomaterial‐based brain delivery systems, they warrant further investigations to better understand the mechanisms underlying GO immunomodulatory properties in brain.
This work was partly supported by the EU H2020 RTD Framework Program: FET Graphene Flagship project (GrapheneCore3, Grant agreement ID: 881603), the Centre National de la Recherche Scientifique (CNRS), the International Center for Frontier Research in Chemistry (icFRC), and the Agence Nationale de la Recherche (ANR) through the LabEx project Chemistry of Complex Systems (ANR‐10‐LABX‐0026_CSC). M.P., as the recipient of the AXA Carbon Bionanotechnology Chair, is grateful to the AXA Research Fund for financial support. MP was also supported by the Spanish Ministry of Economy and Competitiveness MINECO (project CTQ2016‐76721‐R), the University of Trieste, and the Spanish State Research Agency (Maria de Maeztu Units of Excellence Program Grant No. MDM‐2017‐0720). Financial support to this project was partially provided by the Fondazione Cariverona (“Verona Nanomedicine Initiative”) and funding from an intramural (University of Verona) international cooperation program (“CooperInt”) was obtained. K.K. would like to acknowledge the Severo Ochoa Centre of Excellence Award to ICN2.