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bioRxiv · 10.64898/2026.03.22.713512

Mucin-binding protein shuttles enable delivery of brain-targeted therapeutics

Shi, S. M.·Tender, G. S.·Xiong, J.·Buff, J. K.·Park, H. I.·Mendiola, J. H.·Wilson, E. N.·Abu-Remaileh, M.·Bertozzi, C. R.·Wyss-Coray, T.
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Abstract

The blood-brain barrier (BBB) poses a major obstacle to the delivery of therapeutics into the central nervous system (CNS) due to its highly restrictive permeability. Here, we introduce glycan-targeted delivery vehicles, or GlycoShuttles, that traverse the BBB by harnessing the cerebrovascular glycocalyx, a carbohydrate-rich layer lining the BBB lumen. We discover that mucin-domain glycoproteins within this structure serve as novel entry portals for brain delivery and engineer mucin-binding protein shuttles that enable efficient transport of diverse molecular cargo across the BBB into multiple key brain cell types. This modular platform facilitates enhanced brain delivery of a variety of payloads, including antibodies and lysosomal proteins, and demonstrates therapeutic efficacy in mouse models of dementia. Our findings establish mucin-targeted GlycoShuttles as a versatile platform for noninvasive brain delivery of therapeutics, opening new avenues for the treatment of CNS diseases.

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Shi, S. M., Tender, G. S., Xiong, J., Buff, J. K., Park, H. I., Mendiola, J. H., Wilson, E. N., Abu-Remaileh, M., Bertozzi, C. R., Wyss-Coray, T.. 2026-03-25. Mucin-binding protein shuttles enable delivery of brain-targeted therapeutics. https://doi.org/10.64898/2026.03.22.713512

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