Potential of intranasal delivery of human mesenchymal stem cells and extracellular vesicles for stroke therapy.

Cerebral ischemic stroke, caused by interrupted cerebral blood flow, remains a leading cause of mortality and long-term disability worldwide. Current FDA-approved therapies-intravenous tissue-type plasminogen activator (tPA) and mechanical thrombectomy-are constrained by narrow time windows (4.5-24 h) and limited accessibility. Mesenchymal stem cells (MSCs) have emerged as promising candidates for neurorestoration, yet their therapeutic efficacy is hindered by poor blood-brain barrier (BBB) penetration and systemic entrapment. Increasing evidence indicates that MSCs exert their therapeutic effects primarily through paracrine mechanisms mediated by extracellular vesicles (EVs), which regulate inflammation, apoptosis, neurogenesis, and angiogenesis. However, translation of EV-based therapies from bench to bedside remains limited, largely due to inefficient delivery and the invasiveness of existing routes. Intranasal (IN) administration offers a minimally invasive approach to bypass the BBB and achieve direct, repeated delivery to the brain. This review synthesizes the mechanistic foundations, preclinical progress, and translational potential of intranasal delivery of MSCs and their EVs for ischemic stroke therapy. We highlight comparative analyses of biodistribution, cellular targets, and functional outcomes across administration routes, emphasizing how route optimization governs therapeutic efficacy. Collectively, these insights establish intranasal delivery as a practical platform for next-generation, cell-free regenerative therapies targeting ischemic brain injury. STATEMENT OF SIGNIFICANCE: Despite extensive investigation of stem-cell-based interventions for ischemic stroke, the influence of administration route on therapeutic outcomes remains poorly defined. This review integrates preclinical and early-phase clinical findings to delineate how delivery pathways shape biodistribution, mechanistic engagement, and neurorepair efficacy of human mesenchymal stem cells (hMSCs) and their derived extracellular vesicles (EVs). By contrasting conventional intravenous and intra-arterial approaches with the emerging intranasal route, this article emphasizes a non-invasive strategy capable of bypassing the blood-brain barrier, supporting multidose regimens, and sustaining localized repair. Beyond summarizing outcomes, this work clarifies mechanistic drivers-angiogenesis, neurogenesis, and immunomodulation-that can be fine-tuned through delivery design. The synthesis provides a framework for rationally optimizing cell-free hMSC-EV therapeutics and underscores the translational promise of intranasal delivery for clinical stroke management.