This study investigates the role of Caspase-11 in Chronic Kidney Disease (CKD) and examines the therapeutic potential of inhibiting Caspase-11 using exosome-mediated siRNA. We established a CKD rat model and analyzed the expression of Caspase-11 through immunohistochemistry. The study involved overexpressing Caspase-11 using an adeno-associated virus (AAV) and constructing exosomes loaded with siRNA targeting Caspase-11 (exo-si-Caspase-11). Renal tissue damage and fibrosis were assessed using H&E staining, Masson's trichrome, TUNEL assay, and Sirius Red staining. Additionally, urinary protein and blood urea nitrogen (BUN) levels were measured, alongside analyses of serum calcium and phosphorus levels. H&E staining was performed to evaluate the effects of exo-si-Caspase-11 on damage to the heart, liver, spleen, and lungs. The results showed that the CKD model group experienced significant weight loss, increased blood pressure, and elevated Caspase-11 expression. AAV-mediated Caspase-11 overexpression led to substantial renal fibrosis, increased apoptosis, and elevated urinary protein and BUN levels. Additionally, the group with Caspase-11 overexpression exhibited elevated serum calcium and phosphorus levels. Conversely, treatment with exo-si-Caspase-11 reduced these pathological changes in renal tissue without causing damage to other major organs. These findings suggest that exosome-mediated siRNA delivery targeting Caspase-11 is an effective therapeutic strategy for CKD.