Peritoneal M2 macrophage-derived extracellular vesicles as a nanotherapeutic for immune-oxidative microenvironment...

IgA nephropathy (IgAN) remains a leading cause of primary glomerulonephritis and end-stage renal disease worldwide, and is characterized by intertwined immune-inflammatory and oxidative injury. In this study, we evaluated the therapeutic potential of M2 macrophage-derived extracellular vesicles (EV_M2) isolated from polarized peritoneal macrophages. In a murine IgAN model, three weeks of EV_M2 treatment significantly improved the survival and body weight, reduced proteinuria, UACR, serum creatinine, and BUN, and alleviated mesangial expansion, podocyte effacement, fibrosis and mesangial IgA deposition. Proteomic profiling revealed that EV_M2 shifted the renal protein signature toward a healthy state with enrichment of redox balance pathways and downregulation of pathways associated with fibrosis, innate immunity and inflammatory responses. EV_M2 also reduced renal mitochondrial ROS, increased SOD2 expression, and restored PI3K/AKT phosphorylation in LPS-injured podocytes. In parallel, EV_M2 decreased the renal M1/M2 macrophage ratio, increased regulatory T-cell accumulation, and reduced inflammatory cytokine expression. Collectively, these results demonstrate that EV_M2 effectively attenuates renal injury in IgAN by mitigating oxidative stress and restoring immune homeostasis, supporting peritoneal macrophages as an accessible source for therapeutic EV production.