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

bioRxiv : the preprint server for biology
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Sophia M Shi, Gabrielle S Tender, Jian Xiong, Josephine K Buff, Hannah I Park, Justin H Mendiola, Edward N Wilson, Monther Abu-Remaileh, Carolyn R Bertozzi, Tony Wyss-Coray

bioRxiv [Preprint]. 2026 Mar 25:2026.03.22.713512. doi: 10.64898/2026.03.22.713512.

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.

PMID:41929072 | PMC:PMC13041825 | DOI:10.64898/2026.03.22.713512