Auto-loaded polydopamine-M2 exosomes as an antioxidative nanoscavenger for lupus erythematosus therapy.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multisystem inflammation and immune dysregulation, predominantly affecting women of reproductive age. Current treatments, including antimalarials, corticosteroids, and immunosuppressants, often entail long-term toxicity. To address this, we developed an auto-loaded polydopamine-M2 exosome system (M2/pEXO) as an antioxidative nanoscavenger for SLE therapy. Ultrasmall PDA nanoparticles facilitated M2 macrophage polarization and were autonomously encapsulated into exosomes during polarization, yielding M2/pEXO with enriched protein content and enhanced cellular uptake. Proteomic analysis indicated that M2/pEXO cargo proteins are involved in cellular energy metabolism and inflammatory regulation, underpinning its immunomodulatory and antioxidant functions. Compared with conventional M2 EXO, M2/pEXO exhibited superior antioxidative and anti-inflammatory effects, reducing M1 macrophage polarization and pro-inflammatory cytokine secretion while promoting regulatory T cell expansion. In a murine SLE model, M2/pEXO significantly alleviated lupus nephritis, attenuating renal immune infiltration, glomerular mesangial proliferation, proteinuria, serum creatinine, and anti-dsDNA autoantibody levels, without detectable toxicity. The platform elevates M2 EXO from mere anti-inflammatory carriers to an integrated nanoscavenger system capable of targeted delivery, oxidative stress scavenging, and immunomodulation. This auto-loaded, naturally engineered strategy presents a safe and effective therapeutic approach for SLE and potentially other chronic inflammatory diseases.