A Single‐Cell Atlas‐Inspired Hitchhiking Therapeutic Strategy for Acute Pancreatitis by Restricting ROS in Neutrophils

Abstract Neutrophils can undergo transcriptional and epigenetic reprogramming in disease, thus causing inflammation or modulating tissue repair and fibrosis. A thorough understanding of the neutrophil subpopulation composition and their polarization processes in acute pancreatitis (AP) is essential to open up design of treatments tailored to individual patients. Herein, this study distinct subgroups and two differentiation pathways associated with N1 and N2 polarization during AP by single‐cell sequencing. Inspired by this, a hollow manganese dioxide (HMnO2)‐based nanoreactor (Pyp@APHM) conjugated with neutrophil‐binding Ly‐6G antibody and loaded with porphyrin is developed for targeted and in situ modulation of neutrophil polarization. Pyp@APHM can enrich the AP site by hitchhiking on neutrophils and then degrade in response to a weakly acidic environment to simultaneously release manganese ions and porphyrin ligands, enabling in situ synthesis of manganese porphyrin antioxidants. Leveraging this strategy, Pyp@APHM can effectively eliminate reactive oxygen species (ROS) and broadly inhibit both N1 and N2 polarization, as well as enhance tissue oxygenation by generating O2, thereby further mitigating pancreatic inflammation. This study provides a comprehensive single‐cell atlas of neutrophils in AP and proposes an innovative hitchhiking therapeutic strategy for AP by restricting ROS in neutrophils.