20% acute pancreatitis (AP) develops into severe AP (SAP), a global health crisis, with an increased mortality rate to 30%-50%. Mitochondrial damage and immune disorders are direct factors, which exacerbate the occurrence and progression of AP. So far, mitochondrial and immunity injury in SAP remains largely elusive, with no established treatment options available. Immunomodulation is a promising approach to treat pancreatitis. Herein, we proved that Tuftsin (TN), a vital endogenous immunomodulator, can inhibit SAP, while it is limited by extremely short biological half-life, low bioavailability, and the inconvenience of administration. Nano platform is the positive choice. Interestingly, we found that the activated P2X7 signaling was closely associated with the enhanced pancreatic inflammation via damaging mitochondrial function in SAP. Herein, we engineered a nanoplatform containing a Se-Se bond responsive for ROS to deliver TN, namely, DSPE-Se-Se-MPEG@TN (DSSM@TN), contributing to increases in TN's half-life and bioavailability. We synthesized TN-loaded ROS-responsive DSPE-Se-Se- MPEG@TN liposomes (DSSM@TN NPs) via a one-step emulsification method, which exhibited good biosecurity, high stability, suitable size, favorable ROS responsiveness and biocompatibility, as well as excellent capability for releasing TN during oxidative stress and inflammation environment. Moreover, the Se-Se bond with ROS-responsive ability was first proved to play a vital role for TN-loaded liposomes to enhance its anti-inflammation and antioxidant abilities via targeting damaged mitochondria during SAP progression. Mechanistically, DSSM@TN targeting damaged pancreas simultaneously inhibits mitochondrial dysfunction and inflammation in vivo and vitro via mitochondrial P2X7 signaling-impaired Nrf2/HO-1 signaling-inhibited PINK1/PARKIN pathway. Consequently, such a ROS-responsive immunotherapy nanomedicine targeted mitochondria holds great potential in facilitating substantial clinical progress in SAP treatment.