Manganese-loaded carbon nanoparticles ameliorate ANCA-associated vasculitis by inhibiting ferroptosis

Antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN), a life-threatening vasculitis manifestation, involves systemic endothelial injury and rapid renal decline. Despite limited therapies, the role of ferroptosis, a newly characterized form of regulated cell death, in ANCA-GN remains unexplored. Here, elevated neutrophil extracellular traps (NETs) were identified in ANCA-GN patients and experimental vasculitis models, correlating with endothelial injury markers. Mechanistically, NETs triggered ferroptosis in glomerular endothelial cells (GEnCs) by suppressing manganese superoxide dismutase (MnSOD) activity, exacerbating oxidative stress. To address this, manganese-loaded glucose-based carbon nanoparticles (GCNPs/Mn) were synthesized, demonstrating biocompatibility and antioxidant properties. In vitro, GCNPs/Mn restored MnSOD activity, mitigated mitochondrial dysfunction, and suppressed NF-κB signaling, reversing NET-induced ferroptosis. In ANCA-GN rat models, GCNPs/Mn administration reduced renal injury, lipid peroxidation, and ferroptosis-related protein dysregulation. Mechanistic studies revealed lysosomal Mn release from GCNPs/Mn enhanced MnSOD activity, linking its therapeutic efficacy to antioxidant defense. This study identifies ferroptosis as a novel driver of GEnC injury in ANCA-GN and pioneers GCNPs/Mn as a MnSOD-targeted nanotherapy, bridging critical gaps in understanding and treating this rare disease.