{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T09:46:50Z","timestamp":1785836810737,"version":"3.56.0"},"reference-count":152,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Brazilian Council for Scientific and Technological Development"},{"name":"the Rio de Janeiro State Research Foundation"},{"name":"the Department of Science and Technology\/Brazilian Ministry of Health"},{"name":"the Coordination for the Improvement of Higher Education Personnel"},{"name":"the National Institute of Advanced Technologies in Diagnosis and Prognosis of Chronic and Neglected Diseases","award":["INATEC-408142\/2024-3"],"award-info":[{"award-number":["INATEC-408142\/2024-3"]}]},{"name":"National Institute of Gene Therapy","award":["INTERGEN-406018\/2022-7"],"award-info":[{"award-number":["INTERGEN-406018\/2022-7"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Sepsis is a life-threatening syndrome characterized by severe immune dysregulation, frequently culminating in acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI). Current supportive therapies fail to reverse the underlying pathophysiological damage. However, mesenchymal stromal cells (MSCs) have emerged as a promising therapeutic frontier due to their robust immunomodulatory, anti-inflammatory, and tissue-regenerative properties. Despite compelling preclinical evidence, translating these benefits into consistent clinical efficacy remains a major challenge. This review critically examines the biological and anatomical barriers limiting the efficacy of MSCs, particularly the pulmonary first-pass effect, which restricts the systemic delivery of viable cells to distant organs such as the kidneys. To overcome these physical limitations, we highlight the recent paradigm shift toward nanoscale, cell-free therapies, specifically MSC-derived extracellular vesicles (MSC-EVs). EVs effectively bypass pulmonary sequestration and thromboembolic risks, exerting their potent therapeutic effects through the horizontal transfer of bioactive cargo, notably microRNAs, to reprogram cellular fate and restore immune homeostasis. We also discuss the critical need for rigorous clinical trial designs, scalable good manufacturing practice protocols, and the integration of a precision medicine approach. Ultimately, incorporating validated biomarkers for targeted patient stratification will be the decisive step in unlocking the full therapeutic potential of MSCs and their derivatives in critical care.<\/jats:p>","DOI":"10.3390\/ijms27156990","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T09:15:22Z","timestamp":1785834922000},"page":"6990","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mesenchymal Stromal Cell-Based Therapies in Sepsis-Induced Acute Lung and Kidney Injury: Current Advances and Perspectives"],"prefix":"10.3390","volume":"27","author":[{"given":"Carla M.","family":"da Silva","sequence":"first","affiliation":[{"name":"Laboratory of Cellular and Molecular Physiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6147-1220","authenticated-orcid":false,"given":"Mayck M. A.","family":"da Silva","sequence":"additional","affiliation":[{"name":"Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3742-2050","authenticated-orcid":false,"given":"Marcelo M.","family":"Morales","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Physiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1093\/infdis\/163.5.937","article-title":"The Ancient Riddle of \u03c3~\u03b7\u03c8\u03b9\u03b6 (Sepsis)","volume":"163","author":"Majno","year":"1991","journal-title":"J. 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