Acute pancreatitis (AP) is a primary contributor to hospitalization and in-hospital mortality worldwide. 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-off between conventional positively charged mitochondrial-targeting groups and their inability to penetrate the blood-pancreas barrier (BPB). Here, a tungsten-based heteropolyacid nano-antioxidant (mTWNDs) is introduced, co-modified with tannic acid (TA) and melanin, enabling site-specific clearance of mtROS in PACs, offering a highly effective treatment for AP. TA exhibits a strong affinity for proline-rich type III collagen and the mitochondrial outer membrane protein TOM20. This unique property allows mTWNDs to traverse the damaged BPB-exposing type III collagen to reach PACs and subsequently penetrate mitochondria for targeted mtROS elimination. In cerulein-induced AP mice, mTWNDs reversed AP at 1/50th the dose of N-acetylcysteine, suppressing PACs apoptosis and inflammation by blocking the stimulator of the interferon genes pathway activation in macrophage. This study establishes a mitochondrial-targeting antioxidant nanomedicine strategy for AP treatment.