Engineered extracellular vesicles targeting BACE1 reduces amyloid beta plaque formation in a genetic mouse model of Alzheimer Disease

Kalluri, V. S.; Che, S.; Conner, M.; Moreno Diaz, B.; Yarlagadda, A.; Church, K. A.; Chronopoulos, A.; Vazquez-Arreguin, K.; Sugimoto, H.; Kalluri, R.

doi:10.64898/2026.08.10.744066

bioRxiv · 10.64898/2026.08.10.744066

Engineered extracellular vesicles targeting BACE1 reduces amyloid beta plaque formation in a genetic mouse model of Alzheimer Disease

Kalluri, V. S.·Che, S.·Conner, M.·Moreno Diaz, B.·Yarlagadda, A.·Church, K. A.·Chronopoulos, A.·Vazquez-Arreguin, K.·Sugimoto, H.·Kalluri, R.

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Abstract

Alzheimers disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-{beta} (A{beta}) plaques, neurodegeneration, and cognitive decline. {beta}-Site amyloid precursor protein cleaving enzyme 1 (BACE1) catalyzes the rate-limiting step in A{beta} production and remains a therapeutic target for AD. However, effective delivery of RNA therapeutics to the brain remains challenging due to the blood-brain barrier (BBB). Here, we evaluated the feasibility of using clinical-grade mesenchymal stem cell-derived extracellular vesicles (EVs) as systemic carriers for Bace1-targeting small interfering RNA (siRNA) in the 5xFAD mouse model of AD. Engineered EVs crossed the BBB and delivered siRNA cargo to the brain, with uptake observed in both neurons and astrocytes. Systemic therapy with EVs engineered to encapsulate Bace1 siRNA resulted in reduced brain Bace1 protein levels and a decrease in amyloid plaque burden compared with control EVs carrying scrambled siRNA. The reduction was most pronounced in larger, high-intensity plaques, suggesting that Bace1 suppression may preferentially limit plaque growth and maturation. Repeated systemic administration was well tolerated, with no evidence of treatment-associated toxicity. These findings establish a proof-of-concept feasibility for EV-mediated delivery of Bace1-targeting siRNA to the brain and support further development of engineered EVs as a therapeutic platform for neurodegenerative diseases. Future studies incorporating behavioral, molecular, and mechanistic analyses will be required to determine the extent to which Bace1 suppression delivered through EVs can modify disease progression and improve functional outcomes in AD.

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Kalluri, V. S., Che, S., Conner, M., Moreno Diaz, B., Yarlagadda, A., Church, K. A., Chronopoulos, A., Vazquez-Arreguin, K., Sugimoto, H., Kalluri, R.. 2026-08-11. Engineered extracellular vesicles targeting BACE1 reduces amyloid beta plaque formation in a genetic mouse model of Alzheimer Disease. https://doi.org/10.64898/2026.08.10.744066

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