Post-capillary venules is the locus for transcytosis of therapeutic nanoparticles to the brain

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SUMMARY 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 and 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 transport of large molecules across the BBB, and targeting therapeutic agents to this locus may be an effective way for treating brain disorders. HIGHLIGHTS Integration of drug carrier nanotechnology with two-photon microscopy in vivo Real-time nanoscale-resolution imaging of nanoparticle transcytosis to the brain Distinct trafficking pattern in the endothelium of cerebral venules and capillaries Venules, not capillaries, is the locus for brain uptake of therapeutic nanoparticles

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