BackgroundKnee osteoarthritis causes pain and disability in many people worldwide, for which no definitive treatment has yet been proposed. In this study, we investigated the safety and efficacy of placental mesenchymal stromal cells-derived extracellular vesicles in patients with knee osteoarthritis.MethodsThis triple-blind, randomized clinical trial included patients suffering from bilateral knee osteoarthritis with grade 2 or 3. The knees of each patient were randomized to intervention and control. For the intervention knee, 5 cc of placental mesenchymal stromal cells-derived extracellular vesicles were injected, and for the control knee, 5 cc of normal saline was injected. The patients’ symptoms were evaluated before the intervention and 2 and 6 months after the intervention using VAS, WOMAC questionnaire, and Lequesne index. MRI was performed before the intervention and 6 months after the intervention to evaluate retropatellar and tibiofemoral cartilage volume, medial and lateral meniscal disintegrity, ACL injury, and effusion-synovitis.Results62 knees (31 patients) were enrolled in this study. There were 31 knees as intervention and 31 knees as control. Finally, the data of 58 knees (29 patients) were analyzed, including 28 women and 1 man. The mean age of the patients was 55.38 ± 6.07 years. No statistically significant difference was detected between the two groups in clinical outcomes (including VAS, WOMAC, and Lequesne scores) before treatment and 2 and 6 months after treatment. Also, no statistically significant difference was detected between the two groups in MRI findings before treatment and 6 months after treatment. No systemic complications or severe local reactions occurred in the patients.ConclusionA single intra-articular injection of placental mesenchymal stromal cells-derived extracellular vesicles (5 cc, 7 × 109 particles/cc) is safe, but does not improve clinical symptoms or MRI findings in knee osteoarthritis beyond placebo. The protocol of this study was approved on 11 May 2022 with registration number IRCT20210423051054N1.