<p>Nowadays, severe acute pancreatitis (SAP) remains a critical clinical disease with a high mortality rate. Current treatments are mainly supportive, lacking specific therapies targeting the core pathological mechanisms including neutrophil extracellular traps (NETs)-mediated systemic inflammation and progressive acinar cell necrosis, which may lead to many complications. Therefore, in this study, we developed a novel dual-targeting nanodrug delivery system named PBs@CCR2-ApopEVs, combining Prussian blue nanoparticles (PBs) and CCR2-overexpressing mesenchymal stem cell-derived apoptotic extracellular vesicles (ApopEVs). Through the specific binding of CCR2 with numerous CCL2 released by neutrophils in SAP, the PBs@CCR2-ApopEVs can be actively recruited to the pancreatic inflammation site. Then PBs effectively inhibit neutrophil extracellular trap (NETs) formation by suppressing myeloperoxidase and elastase expression, as well as Gasdermin D pathway activation, thereby reducing oxidative stress and inflammatory responses. Simultaneously, we confirmed that MSCs-ApopEVs could activate the p-STAT3/SOX4 pathway to promote acinar-to-ductal metaplasia (ADM) process, enhancing the self-protection ability of acinar cells and reducing necrosis. This dual-approach strategy—targeting anti-inflammatory effects externally while reinforcing cytoprotective mechanisms internally—stands out as a novel therapeutic avenue for SAP management, providing a new approach for SAP treatment and significantly improving therapeutic efficacy. </p> Graphical Abstract <p></p>