Multiplex screening of transferrin receptor-targeted lipid nanoparticles for systemic brain delivery using DNA barcodes

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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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