Exosome-Mediated Delivery of a PLD1 Modulator Overcomes Bioavailability Hurdles to Target Synaptopathy in Neurodegenerative Diseases

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.