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

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.