Multiorgan repair by MSC-derived extracellular vesicles in hepatorenal syndrome through necroptosis alleviation, immune reprogramming and fibrosis resolution.

Aim: To investigate the therapeutic potential and underlying mechanism of mesenchymal stem cell (MSC)-derived extracellular vesicles (MSC-EVs) in treating hepatorenal syndrome (HRS), a condition lacking therapies for multi-organ damage. Methods: EVs were isolated from human umbilical cord MSCs and characterized by transmission electron microscopy, nanoparticle tracking analysis, and proteomics. A murine model of HRS, induced by bile duct ligation (BDL), was established, and mice received intravenous MSC-EVs treatment. Therapeutic efficacy was assessed through histopathology, serum biochemistry, and analysis of necroptosis, inflammation, and fibrosis markers. Results: Proteomic profiling of MSC-EVs revealed significant enrichment of proteins involved in renal processes, anti-fibrosis, and immune regulation. In BDL-induced HRS mice, MSC-EVs treatment demonstrated potent multi-organ protective effects. This was evidenced by alleviation of hepatic necroptosis and renal tubular injury, downregulation of interleukin-17 expression, and concurrent attenuation of fibrosis in both liver and kidney tissues. Consequently, significant improvements in hepatic and renal function markers were observed. Conclusion: MSC-EVs represent a novel and effective cell-free nanotherapeutic strategy for HRS. They confer protection through multi-faceted mechanisms, including inhibition of necroptosis, immune reprogramming, and fibrosis resolution, offering a promising paradigm for the treatment of multi-organ failure.