MSC-derived exosomes for hemorrhagic stroke: preclinical evidence and translational challenges

Hemorrhagic stroke, caused by bleeding into the brain parenchyma or subarachnoid space, accounts for 10-20% of cerebrovascular events worldwide. It is classified as intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH). Despite distinct etiologies, both forms initiate a shared injury cascade marked by metabolic failure, mitochondrial dysfunction, oxidative stress, cytotoxic edema, and progressive neuronal loss. Current guidelines prioritize time-sensitive, neuroprotective measures aimed at acute stabilization and complication prevention. However, these interventions remain largely supportive and fail to directly address the sustained secondary injury processes that underlie long-term neurological disability. In this Perspective, we focus on mesenchymal stem/stromal cell (MSCs)-derived exosomes as a promising cell-free therapeutic strategy with distinct advantages over MSC-based therapies. We first provide an overview of the key mechanisms of neuronal injury in hemorrhagic stroke, distinguishing early brain injury from delayed, secondary damage. We then define exosomes within the broader extracellular vesicle landscape and explain why MSC-derived exosomes are emphasized as principal mediators of MSC paracrine effects. Finally, we synthesize preclinical evidence showing that exosomes can attenuate neuroinflammation, limit apoptosis, and promote angiogenesis and neurogenesis, with associated improvements in functional recovery in experimental stroke models. We also highlight unresolved challenges identified in the current literature, including uncertainties surrounding therapeutic timing, dosing strategies, vesicle heterogeneity, and the need for improved in vivo tracking and mechanistic resolution. As the field advances, addressing these critical issues will be essential for translating MSC-derived exosomes into effective therapies for hemorrhagic stroke.