CCR2-mediated chemotactic plant-derived extracellular vesicles for targeting and remodeling the immune microenvironment in cerebral ischemia-reperfusion injury treatment

Abstract

The recruitment of peripheral immune cells into the brain and the subsequent formation of an inflammatory microenvironment are key drivers of cerebral ischemia-reperfusion injury (CIRI). Current nanosystem-based therapeutic strategies primarily target the brain parenchyma, yet often neglect the continuous challenge posed by peripherally derived immune insults. Plant-derived extracellular vesicles (EVs) offer advantages such as facile preparation and immunomodulatory properties, making them attractive for CIRI treatment, but their therapeutic potential is constrained by poor targeting capability. Here, using ginger-derived EVs (GEVs) as a representative, we develop CCR2-mediated chemotactic GEVs (CGEVs) that integrate the chemotactic/blockade functions of the chemokine receptor CCR2 with the anti-inflammatory activity of GEVs to achieve synergistic regulation of both external and internal immune microenvironments in CIRI. Specifically, CGEVs are generated by fusing GEVs with stem cell-derived EVs engineered to overexpress CCR2. CCR2 directs CGEVs to the ischemic lesion, enabling accumulation in the brain via the compromised blood brain barrier. By sequestering infiltrating peripheral immune cells, CGEVs mitigate sustained neuronal damage and reduce immunothrombosis. Furthermore, the resulting CGEVs possess antioxidant and cytoprotective activity, rescuing neurons from apoptosis through scavenging reactive oxygen species and protecting mitochondrial integrity. In a rat model of middle cerebral artery occlusion/reperfusion, treatment with CGEVs reduces infarct size and restores microenvironmental homeostasis. This strategy provides new insights into Plant-derived EVs mediated targeting intervention for CIRI.