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Transferrin-Functionalized Liposomes Enhance MAPT-ASO Transport Across a 3D Blood-Brain Barrier Microvascular Network

Simon Konig1, Xinai Shen2, Giuseppe Mantovani2

  • 1Department of Mechanical Engineering, University College London, London WC1E 6BT, UK.

International Journal of Molecular Sciences
|December 11, 2025
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Summary

Researchers developed transferrin-functionalized liposomes to deliver tau-targeting antisense oligonucleotides (ASO) across the blood-brain barrier (BBB). This novel strategy enhances brain delivery of MAPT-ASO for potential Alzheimer's disease treatment.

Keywords:
Alzheimer’s diseaseantisense oligonucleotides (ASO)blood–brain barrier modelneurotherapeuticstargeted liposomal deliverytau protein

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Area of Science:

  • Neuroscience
  • Biotechnology
  • Drug Delivery

Background:

  • Tau pathology is a key hallmark of Alzheimer's disease (AD), correlating with cognitive decline.
  • Current antisense oligonucleotide (ASO) therapies targeting the MAPT gene show promise but face challenges in crossing the blood-brain barrier (BBB).

Purpose of the Study:

  • To develop and evaluate transferrin (TF)-functionalized liposomes for enhanced delivery of MAPT-ASO across an in vitro BBB model.
  • To assess the therapeutic efficacy and brain delivery potential of TF-functionalized liposomes carrying MAPT-ASO.

Main Methods:

  • Development of transferrin (TF)-functionalized liposomes encapsulating MAPT-ASOs.
  • Utilized a 3D self-assembled microvascular BBB model comprising human brain microvascular endothelial cells, astrocytes, and pericytes.
  • Evaluated MAPT-ASO efficacy in reducing tau levels and protecting against axonal degeneration.
  • Assessed liposome transport and extravascular accumulation across the BBB model over 24 hours.

Main Results:

  • Confirmed MAPT-ASO efficacy in reducing tau and protecting against glutamate-induced axonal degeneration.
  • TF-functionalized liposomes demonstrated significantly enhanced extravascular accumulation and sustained delivery of MAPT-ASO compared to non-functionalized liposomes.
  • Successful transport of MAPT-ASO across the 3D in vitro BBB model was observed.

Conclusions:

  • Transferrin-functionalized liposomes offer a novel and effective strategy for delivering tau-targeting antisense oligonucleotides (ASO) across the BBB.
  • This approach may enable systemic delivery of MAPT-ASO, potentially overcoming limitations of intrathecal administration for Alzheimer's disease treatment.
  • The 3D in vitro BBB model is a valuable tool for screening and optimizing the brain delivery of nucleic acid therapeutics.