Reprogramming M2b Macrophages via GPX1 Activation by Selenium Nanoparticles Attenuates Lupus Nephritis

Abstract

Lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE), is largely driven by dysregulated macrophage responses. However, the heterogeneity of macrophages hinders the development of targeted therapies for LN. Here, through single-cell analysis and clinical specimen validation, it is found that pro-inflammatory M2b macrophages are increased in the kidneys of patients with LN and are strongly associated with clinical indicators. To target and modulate M2b macrophages, mannose-functionalized selenium nanoparticles are engineered that can selectively suppress M2b polarization and activation by reducing reactive oxygen species (ROS), restoring mitochondrial function, and inducing selenoprotein glutathione peroxidase 1 (GPX1). In vivo, SeZM NPs accumulate in the kidneys of lupus mice and reduce M2b-derived pro-inflammatory cytokines, preserving renal structure and function. Together, these findings highlight pro-inflammatory M2b macrophages as pathogenic drivers of LN and demonstrate the translational potential of selenium-based nanotherapy.