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Drug delivery to the brain is oneof the major challenges in thetreatment of cerebral diseases and implies extensive understandingof nanomedicine transcytosis pathways across the blood–brainbarrier (BBB). In this study, we investigated the interaction of squalenoyl-adenosinenanoassemblies (SQAd NAs) with human brain endothelial cells, concerningtheir endocytotic pathway using chemical inhibitors and nanostructureintegrity using Förster resonance energy transfer (FRET). Practically,SQAd NAs were labeled with two different organic dyes as a donor–acceptorFRET pair to form FRET SQAd NAs with diameters of ca. 120 nm. Usingthe human cerebral endothelial cell line, hCMEC/D3, as a well-recognizedBBB model, we demonstrated that the NAs were internalized mainly byLDL receptors-mediated endocytosis, then progressively disassembledinside the cells, and finally exocytosed as single molecules. Theseobservations allow explaining the previously described pharmacologicalefficiency of the SQAd NAs in both a cerebral ischemia model and aspinal cord injury model, confirming that the endothelial cells ofthe neurovascular unit may represent a very promising therapeutictarget for the treatment of certain neurological diseases. [ABSTRACT FROM AUTHOR]