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

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.