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

Tau pathology is a defining hallmark of Alzheimer's disease (AD), closely associated with cognitive decline. Antisense oligonucleotides targeting the tau-encoding gene MAPT (MAPT-ASO) have shown promise in clinical trials, but their therapeutic potential is limited by poor delivery across the blood-brain barrier (BBB). In this study, we developed transferrin (TF)-functionalized liposomes encapsulating MAPT-ASOs and evaluated their transport across a 3D self-assembled microvascular BBB model composed of human brain microvascular endothelial cells, astrocytes, and pericytes embedded in a fibrin hydrogel. Following confirmation of MAPT-ASO efficacy in reducing tau levels and protecting against glutamate-induced axonal degeneration, we observed significantly enhanced extravascular accumulation and sustained delivery of MAPT-ASOs with TF-functionalized liposomes over 24 h, compared to non-functionalized control liposomes. This study presents a novel delivery strategy for a functionally effective tau-targeting anti-sense oligonucleotide (ASO), potentially enabling systemic delivery rather than intrathecal administration. In addition, this study demonstrates the utility of the 3D in vitro BBB model for screening and optimizing brain delivery of nucleic acid-based therapeutics.