Abstract
INTRODUCTION: Inhibition of Phospholipase D1 (PLD1) is a promising therapeutic strategy for Alzheimer's disease (AD) and related dementia (ADRD), yet clinical progress has been stalled by the inability of potent inhibitors to effectively cross the blood-brain barrier (BBB). While next-generation PLD1 inhibitors have failed in preclinical mammalian models due to poor CNS penetration, we revisit our functionally proven inhibitor VU0155069 (or VU01), demonstrating a definitive solution to this delivery challenge. METHODOLOGY: We engineered an exosome/extracellular vesicle (EVs)-based nanocarrier (Exo-VU01) to encapsulate VU0155069, optimizing drug payload via electroporation and confirming vesicle integrity through Nanoparticle Tracking Analysis. The therapeutic potential of this formulation was tested in a head-to-head intravenous pharmacokinetic study against free VU0155069 in mice. RESULTS: Relative to free VU0155069, which exhibited rapid systemic clearance and negligible brain retention, Exo-VU01 achieved approximately 20-fold higher brain area under the curve (AUC), underscoring its potential to optimize drug retention and regional biodistribution within the CNS. CONCLUSION: Our study validates Exo-VU01 as a viable platform for CNS drug delivery. It provides increased efficacy for VU0155069 as a therapeutic candidate for AD/ADRD and establishes a clear translational pathway for targeted delivery.