Hyaluronic Acid‐Chitosan Nanoparticles Encapsulating Gal‐9 Alleviate Severe Acute Pancreatitis by Promoting M2 Macrophage Polarization

ABSTRACT Severe acute pancreatitis (SAP) is a prevalent gastrointestinal disease with no effective treatment to control inflammation currently. Macrophages, particularly peritoneal macrophages (PMOs), play a pivotal role in SAP inflammation by polarizing into M1 or M2 phenotypes, which exhibit distinct functional properties and cytokine expression profiles. Galectin‐9 (Gal‐9) modulates macrophage polarization, but its specific effect on PMOs in SAP remains unclear. In this study, hyaluronic acid‐chitosan nanoparticles encapsulating Gal‐9 (HA‐CS‐Gal‐9 NPs) were developed for delivery. In vitro, HA‐CS‐Gal‐9 NPs enhanced M2 marker expression and suppressed M1 markers in both naive (M0) and LPS‐induced M1 macrophages. In vivo, HA‐CS‐Gal‐9 NPs effectively delivered Gal‐9, showing effective uptake by PMOs without notable toxicity, resulting in reduced IL‐6, and increased IL‐10 expression in PMOs. Treatment with these nanoparticles (NPs) decreased systemic pro‐inflammatory cytokines, thereby alleviating pancreatitis severity. These findings demonstrate that Gal‐9‐loaded NPs robustly promoted M2 macrophage polarization, highlighting a promising therapeutic strategy for SAP.