PDA@MnOx nanozyme-engineered mesenchymal stem cells for severe acute pancreatitis therapy via modulation of ROS-inflammation-microbiota homeostasis

Severe acute pancreatitis (SAP) is a life-threatening inflammatory disorder with an approximate mortality rate of 40%. Current therapeutic approaches fail to address its complex pathological microenvironment, necessitating novel synergistic strategies. Although mesenchymal stem cells (MSCs) exhibit therapeutic potential, their efficacy is significantly compromised by SAP-associated oxidative stress, hyperinflammation, and gut dysbiosis. Herein, we engineered MSCs with antioxidant nanozyme PDA@MnO x , named PDA@MnO x -MSCs ( Abbr. E-MSCs), to establish a regulatory network for SAP therapy. The PDA@MnO x nanozymes not only scavenge reactive oxygen species (ROS) to protect MSCs from oxidative damage but also enable in vivo T 1 -weighted MRI tracking. E-MSCs demonstrated enhanced anti-inflammatory effects, evidenced by reduced levels of TNF-ɑ and IL-6, and restored gut microbiota homeostasis, characterized by increased Bacteroidetes abundance. This further alleviated pancreatic necrosis and systemic inflammation. Notably, the synergistic interaction among PDA@MnO x nanozymes, MSCs, and the pathological microenvironment restored ROS-inflammation-microbiota homeostasis, significantly improving SAP outcomes. This study provides a multifunctional strategy integrating therapeutic efficacy, in vivo tracking, and gut microbiota modulation for SAP treatment. Graphical