Dual-targeted engineered mesenchymal stem cell-derived extracellular vesicles delivering Nedd4 attenuate renal fibrosis in diabetic kidney disease

Renal interstitial fibrosis is a critical feature of renal injury in diabetic kidney disease (DKD), and the degree of fibrosis progressively worsens as the disease advances. Therefore, understanding the complexity of the renal fibrosis microenvironment is vital for improving anti-fibrotic therapeutic outcomes. In this study, we found that CD68 + VEGF + TGF-β 1 + macrophages promote the overexpression of NUAK family SNF1-like kinase 1 (NUAK1) in tubular epithelial cells, as revealed by single-cell transcriptome sequencing. Mechanistically, increased NUAK1 directly binds to Yes1-associated protein (YAP), disrupts its interaction with large tumor suppressor kinase 1 (LATS1), and promotes YAP nuclear translocation, thereby accelerating the progression of DKD fibrosis. In addition, umbilical cord mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) attenuate renal interstitial fibrosis in DKD by inhibiting the NUAK1/YAP pathway. Analysis of conditional Nedd4 loss-of-function transgenic mice showed that MSC-EVs exert anti-fibrotic effects by delivering the E3 ubiquitin ligase Nedd4, which mediates NUAK1 degradation. Furthermore, we constructed dual-targeted engineered MSC-EVs modified with superparamagnetic nanoparticles and loaded with Nedd4 (SPION-EVs-Nedd4), which improved their targeted anti-fibrotic therapeutic effects. Together, these findings provide a new strategy for the prevention and treatment of DKD interstitial fibrosis, with significant scientific value and clinical translational potential.