Exosome-nanomaterial hybrid nanomedicine for ischemic stroke: microenvironment-informed design, therapeutic...

Ischemic stroke (IS) remains a major cause of mortality and long-term disability despite advances in reperfusion therapy, underscoring the need for adjunctive interventions that can operate within the dynamic post-ischemic microenvironment. Exosomes and other extracellular vesicles (EVs) provide a biologically compatible interface for brain delivery, yet native vesicles are constrained by heterogeneous composition, modest loading efficiency, limited targeting control, and manufacturing variability. Exosome-nanomaterial hybrid systems are therefore emerging as modular platforms that integrate exosomal biointerfaces with the tunable payload capacity, imaging compatibility, mechanical stability, and stimulus responsiveness of synthetic nanomaterials. In this review, we propose a microenvironment-informed design paradigm for IS nanomedicine. In this framework, the ischemic lesion is not treated as a passive delivery destination, but as a staged design brief defined by blood-brain barrier (BBB) remodeling, thromboinflammation, oxidative stress, immune-cell trafficking, and neurovascular repair. We summarize how exosome source, nanomaterial component, cargo loading, surface functionalization, administration route, and characterization strategy can be selected according to these pathological cues. We further discuss therapeutic applications in BBB-penetrant delivery, neuroprotection, inflammatory modulation, imaging-guided therapy, and neurovascular recovery, together with safety, quality-control, manufacturing, and regulatory barriers. Overall, exosome-nanomaterial hybrids may become clinically meaningful for IS only when their design is microenvironment-informed, mechanism-driven, and translationally scalable.