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 hours, compared to non-functionalized control liposomes. These findings demonstrate the potential of receptor-targeted liposomal carriers for non-invasive central nervous system (CNS) delivery and underscore the utility of advanced in vitro BBB platforms for preclinical screening of tau-targeted therapeutics in Alzheimer’s disease.