Lupus nephritis is a severe complication of systemic lupus erythematosus, primarily driven by immune cell activation through the NF-kB pathway. This study aims to evaluate the the therapeutic potential of exosome-loaded NF-kB inhibitors in lupus nephritis mouse model. We utilized a spontaneous lupus mouse model, MRL/Mpj/Faslpr/J female mice, as the disease group and age-matched MRL/Mpj female mice as controls. The treatment group received exosomes loaded with the NF-kB inhibitor srIkB intraperitoneally three times a week from 6 to 19 weeks of age. A comparator treatment group received normal saline under the same regimen. Urine samples were collected weekly from week 6 using 24-hour metabolic cage analysis to assess albuminuria progression. At 19 weeks, mice were sacrificed, and kidney, spleen, and blood samples were collected for analysis. Western blot, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, glomerular pathologic scoring were used to evaluate the local and systemic involvement of NF-kB signaling in disease progression and therapeutic effects. Exosomes loaded with the NF-kB inhibitor srIkB did not show protective effects on kidney function as assessed by albuminuria (mean urine albumin-to-creatinine ratio; treatment group: 251.6 mg/g, control group: 379.5 mg/g, P=0.35) and serum creatinine levels (mean creatinine; treatment group: 0.34 mg/dL, control group: 0.37mg/dL, P=0.56). Pathologic findings also demonstrated similar patterns of glomerular damage between groups. Only a significant reduction in mRNA levels of TNF-α, IL-1β, IL-2, and CCL5 was observed in both the spleen and kidney. In conclusion, exosome-mediated delivery of NF-κB inhibitors did not confer renal protection or suppress NF-κB activation in a lupus nephritis mouse model, although modest reductions in pro-inflammatory cytokine expression were observed. These findings suggest that exosome-loaded NF-κB inhibitors alone may be insufficient to ameliorate kidney injury in lupus nephritis.