Table 1_Trends in mesenchymal stem cell-derived extracellular vesicles clinical trials 2014–2024: is efficacy optimal in a narrow dose range?.docx

BackgroundMesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are emerging as promising cell-free therapeutic agents due to their immunomodulatory and regenerative properties. However, the lack of standardized protocols and dose optimization strategies has limited their clinical translation. While procedures for the isolation, expansion, and therapeutic use of mesenchymal stem cells (MSCs) have been standardized, there remains a lack of standardized protocols for the isolation and purification of EVs and exosomes (Exos).
MethodsThis review Comprehensive statistical summary global clinical trials involving MSC-EVs and Exos registered between 2014 and 2024, with a particular focus on dose-effect relationships and administration routes. Data were collected from ClinicalTrials.gov, the Chinese Clinical Trial Registry, and the Cochrane Register of Studies. A total of 66 eligible trials were included after screening.
ResultsIntravenous infusion and aerosolized inhalation were identified as the predominant administration methods, especially in trials targeting respiratory diseases. Notably, dose-effect results revealed that nebulization therapy achieved therapeutic effects at doses around 108 particles, significantly lower than those required for intravenous routes. This suggests a relatively narrow and route-dependent effective dose window. However, large variations in EVs characterization, dose units, and outcome measures were observed across trials, underscoring the lack of harmonized reporting standards.
ConclusionThis review highlights dose-response as a critical but underappreciated gap in current MSC-EVs clinical research. The findings emphasize the urgent need for standardized dosing frameworks, potency assays, and harmonized clinical protocols to advance the safe and effective translation of MSC-EVs therapies. The analysis underscores the need for standardized protocols, global collaboration, and a deeper understanding of the biological mechanisms underlying MSC-EVs and Exos therapies to advance clinical applications and ensure safety and efficacy.

背景：间充质干细胞来源的细胞外囊泡（Mesenchymal stem cell-derived extracellular vesicles, MSC-EVs）凭借其免疫调节与组织再生特性，正成为极具前景的无细胞治疗制剂。然而，标准化方案与剂量优化策略的缺失，限制了其临床转化。尽管间充质干细胞（Mesenchymal stem cells, MSCs）的分离、扩增及治疗应用流程已实现标准化，但细胞外囊泡（extracellular vesicles, EVs）与外泌体（exosomes, Exos）的分离纯化方案仍未统一。
方法：本综述对2014至2024年间注册的、涉及MSC-EVs与Exos的全球临床试验进行了全面统计总结，重点聚焦剂量-效应关系与给药途径。数据源自ClinicalTrials.gov、中国临床试验注册中心以及Cochrane研究注册库。经筛选后，共纳入66项符合标准的临床试验。
结果：研究发现，静脉输注与雾化吸入是主流的给药方式，在针对呼吸系统疾病的临床试验中尤为突出。值得注意的是，剂量-效应分析结果显示，雾化给药在约10^8颗粒剂量下即可达到治疗效果，显著低于静脉给药途径所需的剂量，这表明有效剂量窗口相对狭窄且具有给药途径依赖性。然而，不同试验间在EVs表征、剂量单位与结局指标上存在较大差异，凸显了统一报告标准的缺失。
结论：本综述指出，剂量-效应关系是当前MSC-EVs临床研究中一项关键却未受到足够重视的研究空白。研究结果强调，亟需建立标准化的剂量框架、效力检测方法与统一的临床方案，以推动MSC-EVs治疗的安全有效临床转化。本分析同时表明，为推进MSC-EVs与Exos疗法的临床应用并保障其安全性与有效性，亟需制定标准化流程、开展全球协作，并深入阐明其背后的生物学机制。