Post-capillary venules are the key locus for transcytosis-mediated brain delivery of therapeutic nanoparticles

Krzysztof Kucharz*, Kasper Kristensen, Kasper Bendix Johnsen, Mette Aagaard Lund, Micael Lønstrup, Torben Moos, Thomas Lars Andresen, Martin Johannes Lauritzen

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

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Abstract

Effective treatments of neurodegenerative diseases require drugs to be actively transported across the blood-brain barrier (BBB). However, nanoparticle drug carriers explored for this purpose show negligible brain uptake, and the lack of basic understanding of nanoparticle-BBB interactions underlies many translational failures. Here, using two-photon microscopy in mice, we characterize the receptor-mediated transcytosis of nanoparticles at all steps of delivery to the brain in vivo. We show that transferrin receptor-targeted liposome nanoparticles are sequestered by the endothelium at capillaries and venules, but not at arterioles. The nanoparticles move unobstructed within endothelium, but transcytosis-mediated brain entry occurs mainly at post-capillary venules, and is negligible in capillaries. The vascular location of nanoparticle brain entry corresponds to the presence of perivascular space, which facilitates nanoparticle movement after transcytosis. Thus, post-capillary venules are the point-of-least resistance at the BBB, and compared to capillaries, provide a more feasible route for nanoparticle drug carriers into the brain.

Original languageEnglish
Article number4121
JournalNature Communications
Volume12
Issue number1
Number of pages17
ISSN2041-1723
DOIs
Publication statusPublished - 2021

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