Stroke is increasingly understood as a systemic disorder rather than a brain-only lesion. Beyond the initial cerebral ischemic insult, rapid autonomic and neuroendocrine stress responses destabilize peripheral organ homeostasis and promote widespread immune and metabolic remodeling. Subsequent barrier failure and peripheral immune dysregulation can generate a sustained “second hit” in which circulating microbial products, damage-associated signals, and inflammatory mediators feedback to amplify neuroinflammation in a blood–brain barrier–vulnerable state. Meanwhile, post-stroke immunity is temporally plastic: inflammatory programs that worsen acute injury can later support resolution and repair, indicating that outcomes depend on immune balance and timing, not simply inflammatory magnitude. Stem cell–derived extracellular vesicles (EVs) are emerging as multi-cargo biologics with consistent preclinical benefit across functional, histological, and inflammatory endpoints. However, clinical translation has progressed slowly, in part because development has largely prioritized strategies to enhance central nervous system delivery even though systemically administered vesicles typically show low exposure in brain parenchyma. Here, we propose a “periphery-first” therapeutic strategy that reframes this pharmacokinetic profile as an advantage. By leveraging the natural sequestration of systemically delivered vesicles by reticuloendothelial and barrier-associated organs—particularly the liver, spleen, and gut—this approach aims to reprogram peripheral immune trajectories, strengthen barrier integrity, and suppress humoral amplification loops that sustain secondary brain injury. We synthesize evidence for stroke-driven multi-organ dysfunction and phase-dependent immune remodeling and integrate mechanistic plausibility for EVs acting through complementary routes: peripheral immune and metabolic rebalancing, actions at the blood–brain barrier interface and limited but potentially meaningful effects within central nervous system immune niches. We also summarize the emerging clinical landscape of EV interventions in stroke and highlight key translational constraints, including product heterogeneity and potency-linked quality control, comorbidity-relevant modeling aligned with systemic pathology, dosing and safety limitations imposed by hepatic clearance, and the need for artifact-resistant biodistribution methods and causal necessity/sufficiency study designs to quantify route-to-efficacy. A periphery-first framework positions EV therapy as a systems-level intervention that targets peripheral drivers of secondary brain injury. Establishing quantitative causal mechanisms and translation-ready manufacturing and dosing principles will be essential to accelerate clinical development beyond a primarily brain-delivery paradigm.
Zhang et al. (Mon,) studied this question.