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We thank Dr. Michele Dipalo (Istituto Italiano di Tecnologia, Genova, Italy) for help with Raman measurements. We also thank Ilaria Dallorto, Rossana Ciancio, Diego Moruzzo, and Arta Mehilli for administrative and technical help. The project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement No. 881603 Graphene Flagship Core3 (to F.B.), the Italian Ministry of Foreign Affairs and International Cooperation (Grant Agreement No. MAE00694702021-05-20 to F.B.), and IRCCS Ospedale Policlinico San Martino, Genova, Italy (Ricerca Corrente and “5x1000” to F.B and V.C.)., Materials and methods and additional figures on materials characterization, in vitro experiments, imaging and mass spectrometry analysis. The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.nano- lett.3c00377. Materials and methods and additional figures on materials characterization, in vitro experiments, imaging and mass spectrometry analysis (PDF) https://pubs.acs.org/doi/suppl/10.1021/acs.nanolett.3c00377/suppl_file/nl3c00377_si_001.pdf Supplementary File P1: Full list of quantified proteins (XLSX) Supplementary File P2: Full sets of altered proteins (XLSX) Supplementary File P3: Full sets of altered proteins (XLSX), Thanks to their biocompatibility and high cargo capability, graphene-based materials (GRMs) might represent an ideal brain delivery system. The capability of GRMs to reach the brain has mainly been investigated in vivo and has highlighted some controversy. Herein, we employed two in vitro BBB models of increasing complexity to investigate the bionano interactions with graphene oxide (GO) and few-layer graphene (FLG): a 2D murine Transwell model, followed by a 3D human multicellular assembloid, to mimic the complexity of the in vivo architecture and intercellular crosstalk. We developed specific methodologies to assess the translocation of GO and FLG in a label-free fashion and a platform applicable to any nanomaterial. Overall, our results show good biocompatibility of the two GRMs, which did not impact the integrity and functionality of the barrier. Sufficiently dispersed subpopulations of GO and FLG were actively uptaken by endothelial cells; however, the translocation was identified as a rare event., European Union's Horizon 2020 Research and Innovation Programme 881603, Ministry of Foreign Affairs and International Cooperation (Italy) MAE00694702021-05-20, IRCCS Ospedale Policlinico San Martino, Genova, Italy