Extracellular vesicles: Revolutionizing targeted therapy for ischemic stroke

Ischemic stroke (IS) remains a leading cause of global death and disability, with treatment effectiveness limited by its complex mechanisms, which include blood-brain barrier (BBB) disruption, neuroinflammation, excitotoxicity, oxidative stress, and cell death. This review summarizes emerging research on extracellular vesicle (EV)-based therapies for IS. EVs, sourced from animals, plants, and microbes, have unique benefits as natural nanocarriers, such as inherent BBB permeability, biocompatibility, and the ability to deliver multiple therapeutic cargos (like miRNAs, proteins, and drugs). We evaluate how EVs target key IS issues: (1) restoring BBB integrity by stabilizing tight junctions (TJs) and reducing matrix metalloproteinases (MMPs), (2) modulating microglia to reduce neuroinflammation, (3) decreasing excitotoxicity, (4) scavenging reactive oxygen species (ROS) to lessen oxidative stress, and (5) inhibiting apoptosis, ferroptosis, and other cell death pathways. Additionally, engineered EVs, such as antibody-conjugated or magnetically guided types, exhibit improved targeting and treatment accuracy, yielding promising results. Despite significant preclinical promise, clinical application faces challenges in standardization, scalable production, and delivery improvement. EVs offer a transformative, multi-targeted approach with the potential to overcome current limitations in IS treatment.