Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.05.133819v1?rss=1 Authors: Kucharz, K., Kristensen, K., Johnsen, K. B., Lund, M. A., Lønstrup, M., Moos, T., Andresen, T. L., Lauritzen, M. J. Abstract: Treatments of neurodegenerative diseases require biologic drugs to be actively transported across the blood-brain barrier (BBB). To answer outstanding questions regarding transport mechanisms, we determined how and where transcytosis occurs at the BBB. Using two-photon microscopy, we characterized the transport of therapeutic nanoparticles at all steps of delivery to the brain at the nanoscale resolution in vivo. Transferrin receptor-targeted nanoparticles were taken up by endothelium at capillaries and venules, but not at arterioles. The nanoparticles moved unobstructed within endothelial cells, but transcytosis across the BBB occurred only at post-capillary venules, where endothelial and glial basement membranes form a perivascular space that can accommodate biologics. In comparison, transcytosis was absent in capillaries with closely apposed basement membranes. Thus, post-capillary venules, not capillaries, provide an entry point for the transport of large molecules across the BBB, and targeting therapeutic agents to this locus may be an effective way for treating brain disorders. Copy rights belong to original authors. Visit the link for more info