Abstract
Achieving widespread delivery of pharmacological agents beyond the blood-brain barrier (BBB) remains a formidable challenge in preclinical and clinical research. Here we quantitatively evaluate and compare three strategies for brain-wide delivery that employ transient BBB disruption or infusion via the cerebrospinal fluid (CSF) in rats. Using molecular magnetic resonance imaging (MRI) techniques, we find that the three techniques produce spatially differentiated labeling patterns, with the most homogeneous delivery produced either using chemically mediated or unfocused ultrasound-based BBB manipulation methods. Contrast enhancement distributions are similar following chemical and ultrasound procedures, but differ notably from the results of intra-CSF infusion. Delivery efficiency using the two BBB disruption methods also correlates inversely with a marker of tight junction density, suggesting that common factors determine susceptibility to these techniques. Our study thus documents the spatial variation of BBB properties across the brain while offering guidance about brain-wide application of molecular technologies in neuroscience and neuromedicine.
Data availability
Processed data are presented in the text, figures, and Supplementary Information. Numerical source data used to generate graphs in this study are provided as an accompanying Supplementary Data file. Raw data for key experiments have been deposited with the Dryad repository at https://doi.org/10.5061/dryad.tqjq2bwb7.
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Acknowledgements
This research was funded by grants from the K. Lisa Yang Brain-Body Center and the NIH (U01 EB031641, R01 NS121073, R01 DA062195) to A.J. M.D., S.B. were partially funded by the MIT Neurobiological Engineering Training Program (NIH T32 EB019940), and S.B. was also funded by a J. Douglas Tan Postdoctoral Fellowship from the McGovern Institute for Brain Research. P.H. was supported by a Wellcome Trust-MIT Postdoctoral Fellowship (105932/Z/14/Z). A.W. was partially funded by the Advanced Multimodal Neuroimaging Training Program at the Massachusetts General Hospital (NIH R90 DA023427). G.G.G. was supported by a travel grant from the Universidad Francisco de Vitoria, and T.K. was funded by a JSPS Postdoctoral Fellowship for Research Abroad.
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M.D., S.B., and P.H. contributed equally. P.H. conceived the study. M.D., S.B., P.H., A.W., H.W., and G.G.G. performed experimental surgeries and imaging. M.D., T.K. performed histology. M.D., S.B. performed imaging analyses. X.W., R.D.K. developed and performed the microfluidic assay. M.D., A.J. wrote the paper with input from other authors. A.J. supervised the research.
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Communications Biology thanks Bilal Syed Nizami and the other anonymous reviewer(s) for their contribution to the peer review of this work. Primary handling editors: Adib Keikhosravi and Benjamin Bessieres. A peer review file is available.
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Dawson, M., Bricault, S., Harvey, P. et al. Quantitative comparison of methods for widespread delivery of small molecules across the blood-brain barrier. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09951-x
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DOI: https://doi.org/10.1038/s42003-026-09951-x
