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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\u2010cell sequencing. Inspired by this, a hollow manganese dioxide (HMnO<jats:sub>2<\/jats:sub>)\u2010based nanoreactor (Pyp@APHM) conjugated with neutrophil\u2010binding Ly\u20106G 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 O<jats:sub>2<\/jats:sub>, thereby further mitigating pancreatic inflammation. This study provides a comprehensive single\u2010cell atlas of neutrophils in AP and proposes an innovative hitchhiking therapeutic strategy for AP by restricting ROS in neutrophils.<\/jats:p>","DOI":"10.1002\/adma.202502200","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T03:51:13Z","timestamp":1747799473000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["A Single\u2010Cell Atlas\u2010Inspired Hitchhiking Therapeutic Strategy for Acute Pancreatitis by Restricting ROS in Neutrophils"],"prefix":"10.1002","volume":"37","author":[{"given":"Deyu","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology Shanghai Institute of Pancreatic Diseases Changhai Hospital, National Key Laboratory of Immunity and Inflammation Naval Medical University  Shanghai 200433 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