The blood-brain barrier has long stood as the ultimate gatekeeper, shielding the central nervous system from toxins and pathogens but also ruthlessly barring entry to over 98 percent of small-molecule drugs and virtually all large biologic therapeutics. This selectivity has rendered conditions like Alzheimer’s, brain cancers, and lysosomal storage diseases extraordinarily difficult to treat, driving scientists to pursue molecular Trojan horses capable of ferrying cargo across endothelial walls. For decades, the field has coalesced around receptor-mediated transcytosis, hijacking nutrient receptors such as the transferrin receptor to usher therapeutic antibodies or enzymes into the brain. However, these systems have been plagued by a persistent translational bottleneck: the antibody shuttles that work beautifully in mice often lose their binding affinity entirely when applied to rats, non-human primates, or humans, forcing researchers to re-engineer new molecules at each step of preclinical development and squandering precious time and resources.
A team led by researchers at the University of California, San Francisco has now unveiled a clever solution that threatens to collapse that bottleneck. In a paper published in Nature Biomedical Engineering, they describe a novel class of antibody shuttles that target CD98hc, the heavy chain of the large neutral amino acid transporter LAT1, which is abundantly and specifically expressed on the luminal surface of brain capillary endothelial cells. LAT1 is the primary route by which essential amino acids like phenylalanine and leucine cross into the brain, and its CD98hc subunit acts as a chaperone essential for the transporter’s trafficking to the cell surface. Because the transporter is an evolutionary ancient and indispensable gateway, its extracellular architecture is remarkably conserved across mammalian species, a fact the UCSF team seized upon to design shuttles with pan-species reactivity.
The group first immunized llamas with recombinant CD98hc extracellular domains from multiple species and panned a phage display library to isolate single-domain VHH antibody fragments, or nanobodies, that bound to human, cynomolgus monkey, rat, and mouse CD98hc with comparable nanomolar affinities. After fusing a lead nanobody to a human IgG1 Fc domain to create a bivalent shuttle, they confirmed that the construct engaged CD98hc on live brain endothelial cells and was rapidly internalized via clathrin-coated pits, followed by efficient transcytosis across polarized monolayers in a microfluidic blood-brain barrier chip. Crucially, the shuttle escaped lysosomal degradation and was released intact on the abluminal side, a trafficking fate that is anything but stochastic—it requires precise sorting into recycling endosomes, a process the CD98hc pathway appears to navigate with high fidelity.
When administered intravenously to mice, the shuttle accumulated in brain parenchyma at levels up to 20-fold higher than a non-targeted IgG control, achieving a brain-to-plasma ratio that surpassed benchmarks set by transferrin receptor shuttles. Immuno-electron microscopy captured the shuttles in the act of traversing endothelial cells, with gold-labeled particles visible inside vesicles at both the luminal and abluminal membranes. The real tour de force, however, came from cross-species comparisons: plasma and brain pharmacokinetics in rats and cynomolgus monkeys revealed strikingly similar brain uptake profiles, with consistent cerebrospinal fluid concentrations that scaled predictably with dose. No species-specific adaptation of the shuttle was required, a finding that the authors argue could slash preclinical development timelines by years.
To demonstrate therapeutic utility, the researchers genetically fused the CD98hc-binding nanobody to iduronate-2-sulfatase, the enzyme missing in Hunter syndrome, a severe lysosomal storage disorder with profound neurological manifestations. In a mouse model of the disease, the enzyme shuttle fusion restored enzyme activity in brain tissue to near-normal levels and significantly reduced the accumulation of heparan sulfate substrates after weekly dosing. Equally important, no overt toxicity, vascular damage, or depletion of serum amino acids was observed, addressing long-standing safety concerns about interfering with the LAT1 transporter’s physiological function. The shuttle appeared to hijack the receptor without impairing its nutrient transport cycle, a delicate balancing act that previous attempts at CD98hc targeting had failed to achieve.
Translational momentum is already building. The UCSF team has humanized the nanobody further and is evaluating its safety profile in a non-human primate toxicology study, with an eye toward an investigational new drug application for enzyme replacement therapies and, in a separate pipeline, for antisense oligonucleotide shuttling. The modular nature of the platform means that the CD98hc shuttle could be appended to a broad suite of payload classes, from gene-editing enzymes to antibody-drug conjugates designed to treat diffuse intrinsic pontine glioma, a pediatric brain tumor that currently has no effective pharmacotherapy precisely because drugs cannot reach it.
Perhaps the most enticing implication is the paradigm shift in how we approach species translation in neuropharmacology. A single shuttle that works predictably from mouse to marmoset to patient not only accelerates clinical timelines but also creates a standardized biological ruler for quantifying brain delivery efficiency, which has long been a missing metric in the field. As regulatory agencies increasingly demand robust pharmacokinetic-pharmacodynamic bridging data, a platform with genuine cross-species fidelity could become an essential component of future CNS drug development programs. While hurdles like large-scale manufacturing, immunogenicity, and long-term transporter safety linger, the CD98hc shuttle stands as a compelling testament to the idea that nature’s most conserved portals may also be medicine’s most versatile keys.
Subject of Research: Development and in vivo validation of CD98hc-targeted antibody shuttles that enable broad cross-species blood-brain barrier transcytosis and CNS delivery of therapeutic payloads.
Article Title: CD98hc-targeted antibody shuttles for central nervous system delivery with broad cross-species reactivity.
Article References:
Wu, WH., Sivaneri, N., Akin, E. et al. CD98hc-targeted antibody shuttles for central nervous system delivery with broad cross-species reactivity.
Nat. Biomed. Eng (2026). https://doi.org/10.1038/s41551-026-01718-3
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41551-026-01718-3
Keywords: blood-brain barrier, CD98hc, receptor-mediated transcytosis, antibody shuttle, CNS drug delivery, cross-species reactivity, large neutral amino acid transporter, nanobody, Hunter syndrome, enzyme replacement therapy
