<p>The therapeutic effect of exosomes (Exo) secreted by the Puerarin-treated umbilical cord mesenchymal stem cells (UC-MSC) on chronic renal failure (CRF) was explored. UC-MSC were treated by Puerarin, or transfected by lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) overexpression vectors, or both. HK-2 cells were treated with LPS/H₂O₂ to establish the CRF cell model. The CRF rat model was constructed by adenine administration. Exo derived from UC-MSC were used to treat the CRF cell and rat models. The therapeutic effect of the Puerarin-treated UC-MSC-derived Exo on CRF was evaluated by a series of logical tests. NEAT1 had binding sites for miR-342-3p. miR-342-3p in the Puerarin-treated UC-MSC-derived Exo was increased. miR-342-3p in the NEAT1-overexpressed and Puerarin-treated UC-MSC-derived Exo was lower than that in the Puerarin-treated UC-MSC-derived Exo. The CRF cell model treated by the Puerarin-treated UC-MSC-derived Exo expressed higher miR-342-3p, and lower TGF-β1, SMAD2/3, Cleaved-caspase-1, GSDMD-N, IL-1β and IL-18. The relieved renal injury, up-regulated renal miR-342-3p, down-regulated renal TGF-β1, SMAD2/3, Cleaved-caspase-1 and GSDMD-N, and decreased serum creatinine and blood urea nitrogen were found in the CRF rat model treated by the Puerarin-treated UC-MSC-derived Exo. However, compared to the CRF cell and rat models treated by the Puerarin-treated UC-MSC-derived Exo, those treated by the NEAT1-overexpressed and Puerarin-treated UC-MSC-derived Exo showed the opposite results. Puerarin elevates exosomal miR-342-3p by suppressing NEAT1 in UC-MSC, thereby inactivating the TGF-β1/SMAD pathway in renal tubular epithelial cells to alleviate pyroptosis in CRF. The Puerarin-treated UC-MSC-derived Exo may be useful in treating CRF.</p>