Pomegranate Seed Oil Biologically Engineered Lactobacillus Extracellular Vesicles with Enhanced Yield and Brain Delivery via ApoE-Enriched Protein Corona.

Abstract

The blood-brain barrier (BBB) is a major bottleneck for nanomedicine-based treatment of central nervous system (CNS) disorders. Lactobacillus-derived extracellular vesicles (LEV) are promising biocompatible nanocarriers, but their low production yield and limited BBB permeability hinder their development. We hypothesized that stimulation of Lactobacillus with pomegranate seed oil (PSO), or its nanoemulsion (PSO NE), could remodel the LEV membrane to simultaneously enhance vesicle production and brain accumulation. Lactobacillus was stimulated with PSO or PSO NE to generate engineered LEV. Lipidomic and proteomic analyses were performed to characterize membrane remodeling and plasma protein corona formation. Oleuropein (OL) was loaded into different LEV formulations, and their BBB permeability and brain accumulation were evaluated in vivo. The anti-amyloid β (Aβ) aggregation activity and biocompatibility of the engineered LEVs were also assessed. PSO and PSO NE increased LEV production by approximately 3- and 5-fold, respectively, while markedly remodeling their membrane composition, with enrichment of phospholipids, triglycerides, and apolipoproteins. Upon exposure to plasma, the remodeled LEVs spontaneously acquired an apolipoprotein E (ApoE)-rich protein corona, facilitating BBB transport through low-density lipoprotein receptor (LDLR)-mediated transcytosis. Accordingly, OL-loaded LEV-PSO and LEV-PSO NE achieved 5-7-fold higher brain exposure than free OL, compared with only a 1.17-fold increase for conventional OL@LEV. Both native and OL-loaded LEVs inhibited Aβ aggregation, with OL-loaded formulations showing stronger activity. Repeated administration for 14 days demonstrated good biocompatibility and significantly increased BBB LDLR expression following LEV-PSO and LEV-PSO NE treatment. PSO-mediated membrane engineering substantially improves LEV production and BBB transport through protein-corona modulation, providing a scalable and versatile platform for CNS drug delivery.

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