<p>Chronic endometritis (CE) is a key factor in adverse pregnancy outcomes such as miscarriage and infertility. Macrophages are an important immune cell type that secrete pro-inflammatory and anti-inflammatory cytokines that are essential for maintaining endometrial function. This study aimed to investigate the key mechanisms by which exosomes derived from adipose-derived mesenchymal stem cells (ADSCs) regulate macrophage polarization through the sirtuin 2 (SIRT2)/NOD-like receptor pyrin containing 3 (NLRP3) axis and exert a protective effect on CE. Exosomes were obtained from ADSCs (ADSCs-exo) using the classical ultracentrifugation method and characterized using transmission electron microscopy, nanoparticle tracking analysis, and western blotting. ADSCs-exo protective effects on CE mice and RAW 264.7 cells and its related molecular mechanisms were investigated using real-time quantitative polymerase chain reaction, western blotting, enzyme-linked immunosorbent assay, flow cytometry, immunofluorescence, immunoprecipitation, hematoxylin and eosin staining, and immunohistochemistry. ADSCs-exo significantly inhibited M1 macrophage polarization, as evidenced by a 54% reduction in tumor necrosis factor alfa (TNF-α), a 46% reduction in interleukin 1β (IL-1β), and a 36% reduction in interleukin 6 (IL-6) levels in LPS-induced RAW264.7 cells. In vivo, ADSCs-exo treatment reduced the expression of TNF-α by 50%, IL-1β by 58%, and IL-6 by 49% in the uterine tissues of CE mice. Moreover, ADSCs-exo upregulated the expression of SIRT2, promoted the deacetylation modification of NLRP3 to inhibit NLRP3 inflammasome activation, and further suppressed M1 macrophage polarization. However, these trends were reversed after SIRT2 silencing. Our experimental results demonstrate that ADSCs-exo alleviate CE by regulating the SIRT2/NLRP3 axis to inhibit M1 macrophage polarization. This provides a potential theoretical basis for the therapeutic role of stem cells in CE.</p>