Multiplex screening of transferrin receptor-targeted lipid nanoparticles for systemic brain delivery using DNA barcodes
Open accessAbstract
Lipid nanoparticle (LNP) encapsulation has shown strong potential for delivering nucleic acid-based medicines (NABMs); however, effective delivery to the central nervous system (CNS) remains challenging. Here, we combined high-throughput screening (HTS) with a targeting antibody fragment (Fab) against the transferrin receptor—a clinically validated mediator of blood-brain barrier (BBB) transcytosis—to rapidly identify LNPs capable of accessing brain parenchyma from systemic circulation. A library of 23 LNPs, each with distinct Fab densities and a unique DNA barcode, was evaluated via a single intravenous injection. Brain and liver biodistribution were quantitatively assessed using PCR and amplicon sequencing, with in situ hybridization and immunofluorescence confirming barcode presence in the brain. The results revealed that Fab density and lipid composition were critical for CNS partitioning. The work described here demonstrates how integrating clinically translatable ligands and in vivo HTS can guide the rational design of LNPs, with the potential to accelerate the discovery of LNP formulations that target the CNS parenchyma.
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Research works printed but not linked: 1
- Canadian Agency for Drugs and Technologies in Health (2019). Clinical Review Report: Patisiran (Onpattro): (Alnylam Netherlands B.V.): Indication: Treatment of polyneuropathy in adult patients with hereditary transthyretin-mediated amyloidosis. https://www.cda-amc.ca/sites/default/files/cdr/clinical/sr0598-onpattro-clinical-review-report.pdf,
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- Authors
- Ghosh, S., Fan, Y., Laufer, B. I., Stephenson, W., Zang, N., Lawrence, J., Lin, H. H., Sen, S., Miller, S. E., Chu, S., Imperio, J., Lubeck, E., Yen, C.-W., Meilandt, W. J., Monson, S., Bingol, B., Friedman, B. A., & Shatz-Binder, W.
- Affiliations
- Genentech
- Corresponding author
- Ghosh, Soumitra
- Shatz-Binder, Whitney
- ORCID
- Venue
- Cell Biomaterials
- Publisher
- Elsevier BV
- Published
- 2026-03
- Volume
- 2
- Issue
- 3
- Pages
- 100303
- ISSN
- 3050-5623 (ISSN-L)
- OpenAlex
- W7117449321
- Cited by
- 3
- References
- 64
- Citations by year
- 2026: 3
- FWCI
- 0.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Biomaterials (publishedVersion, cc-by-nc-nd)
- Funders
- Genentech Inc
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- lipid nanoparticles, transferrin receptor, blood-brain barrier, brain drug delivery, DNA barcodes, high-throughput screening, lipid composition, tissue distribution
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