{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T20:07:39Z","timestamp":1790194059230,"version":"4.1.0"},"reference-count":37,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,6,9]],"date-time":"2024-06-09T00:00:00Z","timestamp":1717891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Taiwan Ministry of Science and Technology","award":["111-2314-B-038-127-MY2"],"award-info":[{"award-number":["111-2314-B-038-127-MY2"]}]},{"name":"Taiwan Ministry of Science and Technology","award":["112-wf-eva-19"],"award-info":[{"award-number":["112-wf-eva-19"]}]},{"name":"Wan Fang Hospital","award":["111-2314-B-038-127-MY2"],"award-info":[{"award-number":["111-2314-B-038-127-MY2"]}]},{"name":"Wan Fang Hospital","award":["112-wf-eva-19"],"award-info":[{"award-number":["112-wf-eva-19"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>This study compared the therapeutic effects of engineered exosomes derived from RAW264.7 cells overexpressing hsa-let-7i-5p (engineered exosomes) to exosomes from human placenta-derived mesenchymal stem cells (hpMSC exosomes) against sepsis-induced acute lung injury. Adult male C57BL\/6 mice were divided into lipopolysaccharide (LPS), LPS plus engineered exosome (LEExo), or LPS plus hpMSC exosome (LMExo) groups, alongside control groups. The results showed that lung injury scores (based on pathohistological characteristics) and the levels of lung function alterations, tissue edema, and leukocyte infiltration in LEExo and LMExo groups were comparable and significantly lower than in the LPS group (all p &lt; 0.05). Furthermore, the levels of inflammation (nuclear factor-\u03baB activation, cytokine upregulation), macrophage activation (hypoxia-inducible factor-1\u03b1 activation, M1 phase polarization), oxidation, and apoptosis were diminished in LEExo and LMExo groups compared to the LPS group (all p &lt; 0.05). Inhibition of hsa-let-7i-5p attenuated the therapeutic effects of both engineered and hpMSC exosomes. These findings underscore the potent therapeutic capacity of engineered exosomes enriched with hsa-let-7i-5p and their potential as an alternative to hpMSC exosomes for sepsis treatment. Continued research into the mechanisms of action and optimization of engineered exosomes could pave the way for their future clinical application.<\/jats:p>","DOI":"10.3390\/jpm14060619","type":"journal-article","created":{"date-parts":[[2024,6,10]],"date-time":"2024-06-10T10:08:43Z","timestamp":1718014123000},"page":"619","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Therapeutic Effects of Engineered Exosomes from RAW264.7 Cells Overexpressing hsa-let-7i-5p against Sepsis in Mice\u2014A Comparative Study with Human Placenta-Derived Mesenchymal Stem Cell Exosomes"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6508-5947","authenticated-orcid":false,"given":"Van Long","family":"Le","sequence":"first","affiliation":[{"name":"International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Department of Anesthesiology and Intensive Care & Emergency Medicine, Hue University of Medicine and Pharmacy, Hue City 52000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5788-5208","authenticated-orcid":false,"given":"Chao-Yuan","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan"},{"name":"Integrative Research Center for Critical Care, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9605-9837","authenticated-orcid":false,"given":"Ching-Wei","family":"Chuang","sequence":"additional","affiliation":[{"name":"Integrative Research Center for Critical Care, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan"},{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan"},{"name":"Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syuan-Hao","family":"Syu","sequence":"additional","affiliation":[{"name":"Integrative Research Center for Critical Care, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan"},{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hung-Jen","family":"Shih","sequence":"additional","affiliation":[{"name":"Division of Urology, Department of Surgery, Changhua Christian Hospital, Changhua 500, Taiwan"},{"name":"Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9840-987X","authenticated-orcid":false,"given":"Hong-Phuc","family":"Nguyen Vo","sequence":"additional","affiliation":[{"name":"International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Department of Anesthesiology, College of Medicine, Can Tho University of Medicine and Pharmacy, Can Tho City 900000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minh Nguyen","family":"Van","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care & Emergency Medicine, Hue University of Medicine and Pharmacy, Hue City 52000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Jen","family":"Huang","sequence":"additional","affiliation":[{"name":"Integrative Research Center for Critical Care, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan"},{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan"},{"name":"Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1111\/imr.12499","article-title":"The immune system\u2019s role in sepsis progression, resolution, and long-term outcome","volume":"274","author":"Delano","year":"2016","journal-title":"Immunol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.3389\/fimmu.2020.01722","article-title":"Pulmonary Innate Immune Response Determines the Outcome of Inflammation During Pneumonia and Sepsis-Associated Acute Lung Injury","volume":"11","author":"Kumar","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990\u20132017: Analysis for the Global Burden of Disease Study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1038\/nri1943","article-title":"Apoptosis and caspases regulate death and inflammation in sepsis","volume":"6","author":"Hotchkiss","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5080843","DOI":"10.1155\/2019\/5080843","article-title":"Reactive Oxygen Species-Induced Lipid Peroxidation in Apoptosis, Autophagy, and Ferroptosis","volume":"2019","author":"Su","year":"2019","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1007\/s10753-019-01124-9","article-title":"The NLRP3 Inflammasome and Its Role in Sepsis Development","volume":"43","author":"Danielski","year":"2020","journal-title":"Inflammation"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1089\/ars.2021.0027","article-title":"Oxidative Stress and Endothelial Dysfunction in Sepsis and Acute Inflammation","volume":"35","author":"Joffre","year":"2021","journal-title":"Antioxid. Redox Signal."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/S1473-3099(21)00773-8","article-title":"Updates in sepsis management","volume":"22","author":"Mushtaq","year":"2022","journal-title":"Lancet Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1517\/13543784.9.7.1651","article-title":"Anti-inflammatory therapies in sepsis and septic shock","volume":"9","author":"Freeman","year":"2000","journal-title":"Expert. Opin. Investig. Drugs."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5985209","DOI":"10.1155\/2017\/5985209","article-title":"Role of Oxidative Stress and Mitochondrial Dysfunction in Sepsis and Potential Therapies","volume":"2017","author":"Mantzarlis","year":"2017","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s41581-018-0023-5","article-title":"Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases","volume":"14","author":"Shi","year":"2018","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1002\/sctm.19-0446","article-title":"The emerging antioxidant paradigm of mesenchymal stem cell therapy","volume":"9","author":"Stavely","year":"2020","journal-title":"Stem Cells Transl. Med."},{"key":"ref_13","first-page":"963689720969186","article-title":"Mesenchymal Stromal Cells Attenuate Infection-Induced Acute Respiratory Distress Syndrome in Animal Experiments: A Meta-Analysis","volume":"29","author":"Wang","year":"2020","journal-title":"Cell Transplant."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1136964","DOI":"10.3389\/fimmu.2023.1136964","article-title":"Mesenchymal stem cell-derived exosomes for treatment of sepsis","volume":"14","author":"Homma","year":"2023","journal-title":"Front. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.7150\/ijms.35369","article-title":"Exosomes Released by Bone Marrow Mesenchymal Stem Cells Attenuate Lung Injury Induced by Intestinal Ischemia-Reperfusion via the TLR4\/NF-\u03baB Pathway","volume":"16","author":"Liu","year":"2019","journal-title":"Int. J. Med. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"84","DOI":"10.21037\/sci.2017.09.06","article-title":"Clinical potential of mesenchymal stem\/stromal cell derived extracellular vesicles","volume":"4","author":"Giebel","year":"2017","journal-title":"Stem Cell Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s13054-019-2339-3","article-title":"Exosomes from endothelial progenitor cells improve outcomes of the lipopolysaccharide-induced acute lung injury","volume":"23","author":"Zhou","year":"2019","journal-title":"Crit. Care"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Chiang, M.D., Chang, C.Y., Shih, H.J., Le, V.L., Huang, Y.H., and Huang, C.J. (2022). Exosomes from Human Placenta Choriodecidual Membrane-Derived Mesenchymal Stem Cells Mitigate Endoplasmic Reticulum Stress, Inflammation, and Lung Injury in Lipopolysaccharide-Treated Obese Mice. Antioxidants, 11.","DOI":"10.3390\/antiox11040615"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Krylova, S.V., and Feng, D. (2023). The Machinery of Exosomes: Biogenesis, Release, and Uptake. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021337"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1157793","DOI":"10.3389\/fimmu.2023.1157793","article-title":"Mesenchymal stem cell-derived exosome alleviates sepsis- associated acute liver injury by suppressing MALAT1 through microRNA-26a-5p: An innovative immunopharmacological intervention and therapeutic approach for sepsis","volume":"14","author":"Cai","year":"2023","journal-title":"Front. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Chang, C.-Y., Chen, K.-Y., Shih, H.-J., Chiang, M., Huang, I.-T., Huang, Y.-H., and Huang, C.-J. (2021). Let-7i-5p Mediates the Therapeutic Effects of Exosomes from Human Placenta Choriodecidual Membrane-Derived Mesenchymal Stem Cells on Mitigating Endotoxin-Induced Mortality and Liver Injury in High-Fat Diet-Induced Obese Mice. Pharmaceuticals, 15.","DOI":"10.3390\/ph15010036"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"109779","DOI":"10.1016\/j.cellsig.2020.109779","article-title":"Silencing TTTY15 mitigates hypoxia-induced mitochondrial energy metabolism dysfunction and cardiomyocytes apoptosis via TTTY15\/let-7i-5p and TLR3\/NF-\u03baB pathways","volume":"76","author":"Zhang","year":"2020","journal-title":"Cell Signal"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"70","DOI":"10.3350\/cmh.2020.0194","article-title":"The development of mesenchymal stem cell therapy in the present, and the perspective of cell-free therapy in the future","volume":"27","author":"Watanabe","year":"2021","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1093\/bja\/aep336","article-title":"L-type calcium channels are involved in mediating the anti-inflammatory effects of magnesium sulphate","volume":"104","author":"Lin","year":"2010","journal-title":"Br. J. Anaesth."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Fernando, M.R., Jiang, C., Krzyzanowski, G.D., and Ryan, W.L. (2017). New evidence that a large proportion of human blood plasma cell-free DNA is localized in exosomes. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0183915"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/978-1-60761-744-0_18","article-title":"Epigenetic changes in the brain: Measuring global histone modifications","volume":"670","author":"Rumbaugh","year":"2011","journal-title":"Methods Mol. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Chang, C.Y., Hsu, H.J., Foo, J., Shih, H.J., and Huang, C.J. (2020). Peptide-Based TNF-\u03b1-Binding Decoy Therapy Mitigates Lipopolysaccharide-Induced Liver Injury in Mice. Pharmaceuticals, 13.","DOI":"10.3390\/ph13100280"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1097\/SHK.0000000000001549","article-title":"Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Attenuate LPS-Induced ARDS by Modulating Macrophage Polarization Through Inhibiting Glycolysis in Macrophages","volume":"54","author":"Deng","year":"2020","journal-title":"Shock"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1210\/er.2008-0031","article-title":"Ethical issues in stem cell research","volume":"30","author":"Lo","year":"2009","journal-title":"Endocr. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.lfs.2017.11.019","article-title":"Mitochondrial dysfunction in obesity","volume":"192","author":"Costa","year":"2018","journal-title":"Life Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1161\/ATVBAHA.111.244061","article-title":"Transition from obesity to metabolic syndrome is associated with altered myocardial autophagy and apoptosis","volume":"32","author":"Li","year":"2012","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/S0898-6568(00)00149-2","article-title":"LPS induction of gene expression in human monocytes","volume":"13","author":"Guha","year":"2001","journal-title":"Cell Signal."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1089\/ars.2007.1825","article-title":"LPS induces hypoxia-inducible factor 1 activation in macrophage-differentiated cells in a reactive oxygen species-dependent manner","volume":"10","author":"Nishi","year":"2008","journal-title":"Antioxid. Redox Signal."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/ng909","article-title":"Mitochondrial transcription factors B1 and B2 activate transcription of human mtDNA","volume":"31","author":"Falkenberg","year":"2002","journal-title":"Nat. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3183","DOI":"10.7150\/thno.52570","article-title":"Engineering exosomes for targeted drug delivery","volume":"11","author":"Liang","year":"2021","journal-title":"Theranostics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/S0301-472X(03)00110-3","article-title":"HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells","volume":"31","author":"Tammik","year":"2003","journal-title":"Exp. Hematol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/xen.12000","article-title":"Do mesenchymal stem cells function across species barriers? Relevance for xenotransplantation","volume":"19","author":"Li","year":"2012","journal-title":"Xenotransplantation"}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/14\/6\/619\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:56:12Z","timestamp":1760108172000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/14\/6\/619"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,9]]},"references-count":37,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["jpm14060619"],"URL":"https:\/\/doi.org\/10.3390\/jpm14060619","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,9]]}}}