The Dual Roles of Microglia- and Astrocyte-Derived Exosomes in Cerebral Ischemia-Reperfusion Injury: from Intercellular Communication to Therapeutic Prospects.

Cerebral ischemia-reperfusion injury (CIRI) is a complex pathological process characterized by metabolic dysfunction, oxidative stress, neuroinflammation, and structural and functional alterations of the neurovascular unit (NVU). Across different studies, CIRI has been reported to be associated, to varying degrees, with neuronal injury and neurological dysfunction. Increasing evidence suggests that exosomes (EXOs) derived from glial cells, particularly microglia and astrocytes, play critical roles in mediating intercellular communication and regulating injury progression in CIRI. This review systematically summarizes the context-dependent and heterogeneous functions of glia-derived EXOs in CIRI. Microglia-derived EXOs exhibit diverse and context-dependent functions depending on the activation state of donor cells and the surrounding microenvironmental conditions. Under pro-inflammatory conditions, EXOs released from microglia may exacerbate inflammation by carrying cargo components such as circular RNAs (circRNAs) and pro-inflammatory proteins, whereas EXOs associated with reparative states may support tissue recovery through the delivery of functional non-coding RNAs. These cargo components may participate in pathological regulation through multiple signaling pathways. Among them, the nuclear receptor coactivator 4 (NCOA4) axis is associated with ferroptosis, ubiquitin-specific protease 14 (USP14) with proteostasis/apoptosis, and thioredoxin-interacting protein (TXNIP) with inflammasome activity, all of which have been linked to reduced neuronal injury and functional recovery. In addition, M2-type-derived EXOs may participate in the regulation of synaptic plasticity and axonal regeneration by modulating the plexin A2 (PLXNA2)/RhoA/ROCK2 signaling pathway. Astrocyte-derived EXOs (ATC-EXOs) further contribute to NVU regulation. A2-type-derived EXOs have been reported in multiple experimental models to be associated with reduced NLR family pyrin domain containing 3 (NLRP3) inflammasome activity and alterations in the PI3K/Akt and MAPK signaling pathways, accompanied by attenuated inflammatory responses and improved blood-brain barrier (BBB) integrity in these models. Some studies suggest that these effects may be related to the transition of microglial phenotypes toward reparative states; however, sufficient in vivo mechanistic evidence supporting their direct regulatory effects remains lacking. In contrast, neurotoxic astrocytes (A1)-derived EXOs exhibit limited or context-dependent effects. Importantly, exosome function is highly state-dependent and cannot be fully explained by simplified pro-inflammatory microglia anti-inflammatory microglia (M1/M2) or A1/A2 paradigms. Moreover, extracellular vesicle heterogeneity and methodological limitations remain major challenges. Despite promising therapeutic potential, including the ability to cross the BBB and enable multi-target regulation, significant barriers to clinical translation persist, such as delivery efficiency, biodistribution, and standardization. Overall, glia-derived EXOs represent a dynamic and multi-level regulatory system in CIRI and a promising platform for precision therapeutic strategies.