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Updated: Jan 15, 2026
Delivery of Therapeutic siRNA to the CNS Using Cationic and Anionic Liposomes
Published on: July 23, 2016
Exosome-Mediated Delivery of a PLD1 Modulator Overcomes Bioavailability Hurdles to Target Synaptopathy in
Shaneilahi Budhwani1, Sravan Gopalkrishna Shetty Sreenivasamurthy1,2,3, Klarissa H Garza2,3
1Graduate School for Biomedical Sciences, University of Texas Medical Branch, Galveston, TX, USA.
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.
