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Targeted elimination of mitochondrial reactive oxygen species (mtROS) within pancreatic acinar cells (PACs) represents an ideal strategy for treating AP. However, existing drugs fail to overcome the physiological barriers of the pancreas to effectively reach PACs mitochondria due to the trade\u2010off between conventional positively charged mitochondrial\u2010targeting groups and their inability to penetrate the blood\u2010pancreas barrier (BPB). Here, a tungsten\u2010based heteropolyacid nano\u2010antioxidant (mTWNDs) is introduced, co\u2010modified with tannic acid (TA) and melanin, enabling site\u2010specific clearance of mtROS in PACs, offering a highly effective treatment for AP. TA exhibits a strong affinity for proline\u2010rich type III collagen and the mitochondrial outer membrane protein TOM20. This unique property allows mTWNDs to traverse the damaged BPB\u2010exposing type III collagen to reach PACs and subsequently penetrate mitochondria for targeted mtROS elimination. In cerulein\u2010induced AP mice, mTWNDs reversed AP at 1\/50th the dose of N\u2010acetylcysteine, suppressing PACs apoptosis and inflammation by blocking the stimulator of the interferon genes pathway activation in macrophage. This study establishes a mitochondrial\u2010targeting antioxidant nanomedicine strategy for AP treatment.<\/jats:p>","DOI":"10.1002\/advs.202413925","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T09:18:37Z","timestamp":1739524717000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Nanomedicine Penetrating Blood\u2010Pancreas Barrier for Effective Treatment of Acute Pancreatitis"],"prefix":"10.1002","volume":"12","author":[{"given":"Dan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of General Surgery Xiangya Hospital Central South University  Changsha 410008 China"},{"name":"National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University  Changsha 410008 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuya","family":"Wang","sequence":"additional","affiliation":[{"name":"Xiangya School of 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