Heme oxygenase-1-enriched tolerogenic dendritic cell-derived exosomes attenuate lupus nephritis by restoring immune balance and iron homeostasis.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disorder characterized by chronic inflammation, oxidative stress, and multi-organ damage, with lupus nephritis (LN) constituting a major cause of morbidity and mortality. Dysregulated iron metabolism and insufficient expression of heme oxygenase-1 (HO-1), a pivotal antioxidant enzyme regulating iron homeostasis and immune responses, have been implicated in LN pathogenesis. However, therapeutic strategies targeting HO-1 and iron dysregulation remain underexplored. Here, we demonstrate that HO-1 expression is markedly decreased in peripheral blood mononuclear cells from SLE patients, particularly those with LN, correlating inversely with disease activity and markers of iron homeostasis disruption. We established that IL-10 induces tolerogenic dendritic cells (tolDCs) through activation of the Nrf2-HO-1 pathway, concomitant with modulation of iron metabolism and oxidative stress genes. Leveraging this mechanism, we generated HO-1-enriched tolDC-derived exosomes (HO-1high-tolDex) and characterized their immunomodulatory properties in vitro, showing effective suppression of pro-inflammatory cytokines and restoration of iron regulatory gene expression in recipient DCs. In vivo, HO-1high-tolDex administered intravenously preferentially accumulated in kidneys of lupus-prone mice, exhibiting superior stability and targeting compared to parental tolDCs. Repeated dosing ameliorated renal pathology, concomitant with decreased DC activation and pathogenic autoantibody titers. Importantly, HO-1high-tolDex reversed oxidative stress imbalances and normalized iron homeostasis markers, mitigating abnormal renal iron accumulation. These findings establish HO-1high-tolDex as a potent, novel cell-free therapeutic agent that simultaneously modulates immune dysregulation, oxidative stress, and iron metabolism in SLE.