Extracellular vesicles (EVs) are nano-sized membrane-bound particles released from cells and offer promise in cell-based regenerative therapy. Preclinical research has propelled the launch of clinical trials with results from initial studies recently published. A systematic review is needed to evaluate trial designs, outcomes, product characterization and safety profiles to identify barriers and inform future research directions.

A systematic search of the literature was conducted (1946 to September 19, 2024) to identify clinical studies using cell-derived EVs. We extracted aspects of study design, diseases being treated, characteristics of trial subjects, isolation methods and characterization of EVs, details of product administration, main conclusions, and aspects of potential study bias.

Twenty-five published clinical trials were included for analysis. COVID-19 and associated acute respiratory distress syndrome (ARDS) were studied most frequently ( n = 8, 32 %). Wound healing was the second largest disease category ( n = 5, 20 %). Seven studies (28 %) were controlled trials. Mesenchymal stromal cells (MSCs) were the most common source of EVs (20 studies, 80 %), with 494 patients receiving MSC-EVs for various indications. Most trials (68 %, n = 17) used ultracentrifugation as the primary method for EV isolation. An individual patient data meta-analysis of controlled COVID-19/ARDS trials investigating MSC-EVs ( n = 3; 5 intervention groups) revealed an odds ratio (OR) for mortality of 0.46 (95 % CI 0.26 - 0.81; p = 0.0073). The benefits of EVs to improve wound healing are less clear with no controlled studies of MSC-EVs and no clear benefit reported in 2 controlled studies of other cell-based EVs. Although administration of EVs was generally well tolerated, safety conclusions remain preliminary given that only one serious adverse event was explicitly reported, and adverse event reporting was often incomplete.

Clinical trials of cell-derived EVs demonstrate marked heterogeneity but potential promise using MSC-EVs to treat COVID-19/ARDS, although efficacy in wound healing is less clear. More controlled studies are needed to optimize and confirm these initial results and to establish a more definitive understanding of the safety profile of EV therapy.