CA-IV-directed small-molecule shuttle enables targeted brain delivery of biologics
The blood-brain barrier (BBB) presents a challenge for central nervous system (CNS) therapies. Receptor-mediated transcytosis offers a solution, but existing receptor targets are ubiquitous across CNS and peripheral tissues, causing unintended exposure. We identified carbonic anhydrase IV (CA-IV) as a brain-enriched receptor enabling engineered viral capsids to cross the BBB. However, it is unclear whether CA-IV can also mediate non-viral delivery. We thus designed a reactive small-molecule shuttle, derived from an FDA-approved binder, that couples to proteins and oligonucleotides in a single step. We validated the binding of conjugated molecules to multiple mammalian CA-IV orthologs and subsequent internalization in cell-based assays. After systemic dosing, CA-IV-targeted antibody conjugates crossed the BBB in mice and neonatal macaques, preferentially accumulating in the brain and sustaining parenchymal levels for at least 7 days. This BrainCAB (Brain access through Carbonic Anhydrase-binder Bioconjugation) technology offers a compact, modular shuttle for selective and prolonged CNS delivery of large molecules.
Authors
- Shawn Kamboj (ORCID: https://orcid.org/0000-0003-1343-7618)
- Timothy F. Shay (ORCID: https://orcid.org/0000-0001-6591-3271)
- Erin E. Sullivan (ORCID: https://orcid.org/0000-0002-1724-6520)
- Sarah E. Reisman (ORCID: https://orcid.org/0000-0001-8244-9300)
- Alba Carretero‐Cerdán (ORCID: https://orcid.org/0000-0002-8284-6856)
- Viviana Gradinaru (ORCID: https://orcid.org/0000-0001-5868-348X)
- Lillian Campos (ORCID: https://orcid.org/0000-0003-0839-0288)
- Xiaozhe Ding (ORCID: https://orcid.org/0000-0002-0267-0791)
- Philip Boehm (ORCID: https://orcid.org/0000-0002-9171-4636)
- Danielle Mantin (ORCID: https://orcid.org/0000-0001-8576-3549)
- Mona Shahgholi (ORCID: https://orcid.org/0000-0002-8879-4305)
- Seongmin Jang (ORCID: https://orcid.org/0000-0002-9822-6790)
- Xinhong Chen (ORCID: https://orcid.org/0000-0003-0408-0813)
- Fiona Ristic
- Yaping Lei
- Jitendra Sharma
- Cynthia M. Arokiaraj
- Andrew S. Fox
- Bill C. Kavvathas
Institutions
- California Institute of Technology (US)
- Howard Hughes Medical Institute (US)
- University of California, Davis (US)
Publication Details
- Journal
- Nature Chemical Biology
- Published
- 2026-08-26
- DOI
- https://doi.org/10.1038/s41589-026-02294-y
- Primary Topic
- Nanoparticle-Based Drug Delivery
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Vetenskapsrådet
- National Institutes of Health