Brain Targeting Bacterial Extracellular Vesicles Enhance Ischemic Stroke Therapy via Efficient ROS Elimination and Suppression of Immune Infiltration

Ischemic
stroke (IS) as a detrimental neurological disease
is accompanied
by oxidative-stress-induced injury, concurrent inflammatory response,
overactivated brain immune microenvironment, and disruption of the
blood–brain barrier (BBB). This cascade of events ultimately
leads to neuronal death and significantly impairs the recovery of
neurological function. In this study, we presented extracellular vesicles
derived from the gut probiotic Lactobacillus reuteri (LrEVs) integrated with brain targeting, reactive oxygen species
(ROS) scavenging, and reduced infiltration of immune cells for effective
multiple therapeutic interventions of IS. LrEVs inherited peptidoglycan
(PGN) specifically targeted upregulated toll-like receptor 2 (TLR2)
in the injured region of the ischemic brain, achieving the effective
penetration of the BBB and accumulation in the ischemic brain. In
the meantime, LrEVs prevented neuronal apoptosis after stroke by scavenging
ROS overproduction and modulating microglial polarization through
inhibition of the MAPK and NF-κB pathways. Furthermore, LrEVs
inhibited the aggregation of C–C motif chemokine ligand 2 (CCL2),
reduced the infiltration of peripheral immune cells such as macrophages
and neutrophils into ischemic brain tissue, and suppressed the impairment
of BBB, thereby improving the overactivated brain immune microenvironment.
The findings provide a vesicle that combines ROS scavenging and modulation
of the immune microenvironment, showcasing the potential of gut-probiotic-derived
vesicles to treat neurological damage.