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This study explored tanshinone IIA (TSA)-pretreated UCMSC exosomes (T-Exos) to enhance neuroprotection and functional recovery post-SCI. T-Exos were isolated from the TSA-treated UCMSCs. SCI mice received T-Exos, with motor function assessed behaviorally. In vitro and in vivo, microglial NLRP3 inflammasome activity, polarization (M1\/M2), and cytokine release were analyzed. miRNA profiling identified key miRNAs in T-Exos; miR-223\u20135p\u2019s role was validated via inhibition. Mechanistic studies linked miR-223\u20135p to USP8\/NLRP3 using Western blot, qPCR, and co-IP assays. T-Exos improved motor recovery in SCI mice by suppressing NLRP3 inflammasome activation, shifting microglia to anti-inflammatory M2 phenotypes, reducing the level of IL-1\u03b2\/IL-18, and alleviating oxidative stress. miR-223\u20135p was highly enriched in T-Exos, and its inhibition reversed therapeutic effects. Mechanistically, miR-223\u20135p targeted USP8, a deubiquitinase stabilizing NLRP3. By inhibiting USP8, T-Exos reduced NLRP3 levels, dampening neuroinflammation. TSA pretreatment enhances exosomal miR-223\u20135p, which blocks USP8-mediated NLRP3 stabilization, driving microglial M2 polarization and neuroprotection. These findings highlight T-Exos as a targeted therapy for SCI, offering insights into the exosome-mediated modulation of inflammatory microenvironments for neural repair.<\/jats:p>","DOI":"10.1021\/acsami.5c09766","type":"journal-article","created":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:52:57Z","timestamp":1754009577000},"page":"45511-45526","source":"Crossref","is-referenced-by-count":10,"title":["Exosomes Derived\nfrom Tanshinone IIA-Pretreated Umbilical\nCord Mesenchymal Stem Cells Repair Traumatic Spinal Cord Injury by\nmiR-223\u20135p\/USP8\/NLRP3 Axis"],"prefix":"10.1021","volume":"17","author":[{"given":"Guoqiang","family":"Shen","sequence":"first","affiliation":[{"name":"The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University , , ,","place":["Suzhou, Jiangsu, China, 215228"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minhao","family":"Liu","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Nanjing Medical University , , , ,","place":["Nanjing, Jiangsu, China, 210029"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Wang","sequence":"additional","affiliation":[{"name":"Nanjing Medical University , , , ,","place":["Nanjing, Jiangsu, China, 211166"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqiang","family":"Qi","sequence":"additional","affiliation":[{"name":"The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University , , ,","place":["Suzhou, Jiangsu, China, 215228"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaoqi","family":"Cao","sequence":"additional","affiliation":[{"name":"The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University , , ,","place":["Suzhou, Jiangsu, China, 215228"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengshuai","family":"Jin","sequence":"additional","affiliation":[{"name":"The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University , , ,","place":["Suzhou, Jiangsu, China, 215228"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Chen","sequence":"additional","affiliation":[{"name":"The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University , , ,","place":["Suzhou, Jiangsu, China, 215228"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bowen","family":"Wan","sequence":"additional","affiliation":[{"name":"Northern Jiangsu People\u2019s Hospital , , , ,","place":["Yangzhou, Jiangsu, China, 225001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1372-8741","authenticated-orcid":true,"given":"Jun","family":"Gu","sequence":"additional","affiliation":[{"name":"The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University , , ,","place":["Suzhou, Jiangsu, China, 215228"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"issue":"1","key":"2026093015075527700_cit1","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1038\/s41392-023-01477-6","article-title":"Spinal cord injury:\nmolecular mechanisms and therapeutic interventions","volume":"8","author":"Hu","year":"2023","journal-title":"Signal Transduct Target Ther."},{"key":"2026093015075527700_cit2","doi-asserted-by":"publisher","first-page":"17018","DOI":"10.1038\/nrdp.2017.18","article-title":"Traumatic spinal\ncord injury","volume":"3","author":"Ahuja","year":"2017","journal-title":"Nat. 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Neuroinflamm."},{"issue":"3","key":"2026093015075527700_cit22","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1002\/ddr.21898","article-title":"Sodium tanshinone\nIIA sulfonate promotes\nspinal cord injury repair by inhibiting blood spinal cord barrier\ndisruption in vitro and in vivo","volume":"83","author":"Luo","year":"2021","journal-title":"Drug Dev. Res."},{"key":"2026093015075527700_cit23","doi-asserted-by":"publisher","first-page":"105661","DOI":"10.1016\/j.phrs.2021.105661","article-title":"Tanshinone IIA:\nA phytochemical as a promising drug\ncandidate for neurodegenerative diseases","volume":"169","author":"Subedi","year":"2021","journal-title":"Pharmacol.\nRes."},{"key":"2026093015075527700_cit24","doi-asserted-by":"publisher","first-page":"110065","DOI":"10.1016\/j.intimp.2023.110065","article-title":"Tanshinone\nIIA analogue 15a inhibits NLRP3-mediated inflammation by activating\nmitophagy in macrophages to alleviate acute tubular necrosis","volume":"118","author":"Chen","year":"2023","journal-title":"Int. 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