Mesenchymal stromal cell-derived extracellular vesicles as a next-generation therapy for ARDS: mechanisms, advances, and future directions

Acute respiratory distress syndrome (ARDS) is a life-threatening syndrome characterized by diffuse alveolar damage, severe hypoxemia, and dysregulated inflammation. Despite improvements in lung-protective ventilation and supportive care, mortality remains high, highlighting the need for therapies targeting core mechanisms of injury and repair. Mesenchymal stromal cells (MSCs) have demonstrated therapeutic potential largely via paracrine mechanisms, with extracellular vesicles (EVs) emerging as a cell-free alternative that retains key MSC benefits while overcoming limitations related to cell viability, engraftment, and scalability. This review synthesizes current evidence on MSC-derived EVs (MSC-EVs) in ARDS, encompassing mechanisms of action, preclinical efficacy, delivery strategies, and translational challenges. Studies published from 2015 to 2025 were retrieved from PubMed, Web of Science, and ClinicalTrials.gov. Emphasis is placed on immunomodulatory effects, restoration of alveolar – capillary barrier integrity, and transfer of functional proteins, mRNAs, and microRNAs. MSC-EVs represent a promising, disease-modifying therapy with potential to reduce ventilation duration, extracorporeal support, and overall healthcare burden. Key challenges remain, including standardized manufacturing, validated potency assays, and identification of patient selection biomarkers. Integration of bioengineering innovations, GMP-compliant production pipelines, and stratified clinical trial designs will be critical to accelerate translation and enable definitive evaluation in late-phase studies.

急性呼吸窘迫综合征（Acute respiratory distress syndrome, ARDS）是一类以弥漫性肺泡损伤、重度低氧血症及炎症调控异常为特征的危及生命的综合征。尽管肺保护性通气与支持治疗手段已取得进展，但其病死率仍居高不下，凸显了针对损伤与修复核心机制开发治疗方案的迫切需求。间充质基质细胞（Mesenchymal stromal cells, MSCs）已被证实具备治疗潜力，其作用主要通过旁分泌机制实现；而细胞外囊泡（extracellular vesicles, EVs）作为一种无细胞替代方案，在保留MSCs核心获益的同时，规避了细胞活力、植入效率及规模化制备相关的局限。本综述整合了当前关于间充质基质细胞衍生细胞外囊泡（mesenchymal stromal cell-derived extracellular vesicles, MSC-EVs）在ARDS中应用的现有证据，涵盖其作用机制、临床前疗效、递送策略及转化挑战。本综述检索了2015年至2025年间发表于PubMed、Web of Science及ClinicalTrials.gov的相关研究，重点聚焦于免疫调节作用、肺泡-毛细血管屏障完整性的修复，以及功能性蛋白质、信使RNA（messenger RNA, mRNA）与微小RNA（microRNA, miRNA）的转运功能。MSC-EVs是一类极具前景的疾病修饰治疗手段，有望缩短机械通气时长、减少体外支持治疗需求并整体降低医疗负担。目前仍存在若干关键挑战，包括标准化制备流程、经过验证的效价测定方法，以及患者筛选生物标志物的鉴定。整合生物工程技术创新、符合药品生产质量管理规范（Good Manufacturing Practice, GMP）的生产体系及分层临床试验设计，对于加速转化研究并推动其在晚期临床试验中完成确定性评估至关重要。