en Stem Cell Stem Cell Original Original <strong>Introduction</strong>: Most mortality in COVID-19 cases was due to the increased inflammatory cytokines and cytokine storm. As mesenchymal stem cells (MSCs) possess immunomodulatory properties, this study assessed the therapeutic effects of placental MSC-derived extracellular vesicles on the inflammation and pulmonary injury caused by COVID-19.&nbsp;<br> <strong>Methods</strong>: The study was carried out in phases I (safety study, 101 patients) and II (efficacy study, 80 patients) in a randomized, double-blind study at four hospital centers from April 2021 to August 2021. In addition to standard treatments, 15 mL of normal saline solution containing 15&times;109 vesicles was injected intravenously for five consecutive days.<br> <strong>Results</strong>: No reaction or adverse events were observed in any patients. In the intervention group, after 5 days of treatment, patients&rsquo; clinical status and oxygenation improved, and 75% of patients presented an increased SpO2 after 5 days. Besides, inflammatory parameters assessment indicated a 21% decrease in neutrophil-lymphocyte ratio and a 54% reduction in C-reactive protein after day five of the intervention.&nbsp;<br> <strong>Conclusion</strong>: PMSC-derived extracellular vesicles were safe and well-tolerated, down-regulated cytokine storms, and restored oxygenation. Thus, they can be considered a promising therapeutic candidate for severe COVID-19. COVID‐19, Extracellular vesicles, Mesenchymal stromal cell, Placenta-derived mesenchymal stem cell, Acute respiratory distress syndrome 79 88 http://anatomyjournal.ir/browse.php?a_code=A-10-379-1&slc_lang=en&sid=1 Mehdi Jahedi Zargar M.jahedizargar@modares.ac.ir 10031947532846007293 10031947532846007293 No Department of Hematology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran. Saeed Heidari Keshel saeedhey@gmail.com 10031947532846007294 10031947532846007294 No Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Saeid Kaviani kavianis@modares.ac.ir 10031947532846007295 10031947532846007295 No Department of Hematology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran. Mohammad Zahraei mhdzahrayee@yahoo.com 10031947532846007296 10031947532846007296 No Nikan Education & Research center (NERC), West Nikan Hospital, Tehran, Iran. Azadeh Izadyari Aghmiuni azadeh.izadyari@gmail.com 10031947532846007297 10031947532846007297 No Department of Nanobiotechnology, Pasteur Institute of Iran, Tehran, Iran. Ali Amir Savadkoohi alia712000@yahoo.com 10031947532846007298 10031947532846007298 No Department of Anesthesia and Critical Care, Mehrad Hospital, Tehran, Iran. Hamidreza Jamaati hamidjamaati@hotmail.com 10031947532846007299 10031947532846007299 No Chronic Respiratory Diseases Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Mohammad Samet samet_mo@ssu.ac.ir 10031947532846007300 10031947532846007300 No Department of Internal Medicine, Shahid Sadoughi Hospital, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. Mahsa Soufizomorrod M.soufi1986@gmail.com 10031947532846007301 10031947532846007301 No National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran. Mina Soufi Zomorrod m.soufi@modares.ac.ir 10031947532846007302 10031947532846007302 No Department of Applied Cell Science and Hematology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran. Faeze Sadat Heidari ghazal9094@yahoo.com 10031947532846007303 10031947532846007303 No Department of Infectious Diseases, Infectious Diseases Research Center, School of Medicine, Shahid Sadoughi General Hospital, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. Mohamad Reza Mirjalili drmirjalili1@yahoo.com 10031947532846007304 10031947532846007304 No Department of Anesthesia and Intensive Care Medicine, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. Payam Tabarsi Payamtabarsi@yahoo.com 10031947532846007305 10031947532846007305 No Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Mohammadreza Soroush Soroush46@gmail.com 10031947532846007306 10031947532846007306 No Nikan Education & Research center (NERC), West Nikan Hospital, Tehran, Iran. Rasoul Aliannejad aliannejad@tums.ac.ir 10031947532846007307 10031947532846007307 No Department of Pulmonary, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran. Mojtaba Javani S.M.Javani@gmail.com 10031947532846007308 10031947532846007308 No Shahid Sadughi Hospital, Isfahan, Iran. Hosein Shafiii S.M.Javani@gmail.com 10031947532846007309 10031947532846007309 No Shahid Sadughi Hospital, Isfahan, Iran. Mohammad Vasei Mvasei@tums.ac.ir 10031947532846007310 10031947532846007310 No Cell Therapy Based Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Science, Tehran, Iran. Masoud Soleimani Soleim_m@modares.ac.ir 10031947532846007311 10031947532846007311 Yes Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.