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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.

2026-03-25 neuroscience
10.64898/2026.03.22.713512 bioRxiv
Show 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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