MAJOR steps forward in addressing drug delivery gap for neurological disorders in research published using antibody-based Brainshuttle™ technology. Promising therapeutic modalities such as RNA-based antisense oligonucleotides (ASOs) can precisely regulate disease-related genes but face limited clinical utility as they’re unable to cross the blood brain barrier (BBB).
TfR1 Engineering Reveals How ASO Cargo Influences Brain Delivery
Previously, transferrin receptor (tFR1) mediated shuttling has shown encouraging results, but the molecular mechanisms are largely unknown. In this study, researchers optimised tFR1 binding by attaching ASOs to engineered delivery systems (antibody shuttles) to investigate their interaction with endothelial cells with the aim to overcome systemic delivery challenges.
Findings showed that ASO attachment improved binding and uptake for some lower-affinity tFR1-targeting shuttles, but reduced receptor engagement for higher affinity shuttles. This highlights that ASO structure and payload can alter how the antibody binds, enters, and moves through BBB cells.
Dual-Targeting Approach Enhances BBB Transport
Researchers also investigated CD98hc, an alternative BBB receptor as a potential delivery target. It was found that CD98hc followed a different cellular transport pathway, and showed a more favourable response to ASO conjugation. This target helped to avoid degradation pathways and peripheral clearance, positioning CD98hc as a potential alternative for future CNS therapies.
In this study, researchers created a bispecific antibody designed to target both TfR1 and CD98hc simultaneously. The dual targeting system combined the efficient uptake properties of TfR1 with the prolonged cellular residence associated with CD98hc, supporting stronger transport across BBB models.
Engineered Delivery Platforms Support Future CNS Therapies
The delivered ASOs successfully reduced target RNA levels in neuron models, demonstrating functional activity after transport. Researchers highlight that the findings provide design principles for developing improved CNS delivery platforms. Better BBB-crossing technologies could support future treatments for neurological disorders, including neurodegenerative diseases. Further studies are needed to confirm whether the approach translates into improved delivery and efficacy in animal models and clinical settings.
Reference
Sela T et al. Impact of ASO conjugation and receptor binding affinity on intracellular transport of mono- and bispecific TfR- and CD98-Brainshuttle™ variants. mAbs. 2026;DOI:10.1080/19420862.2026.2691351.
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