ABSTRACT Non‐alcoholic fatty liver disease (NAFLD) is a global health burden characterized by hepatic steatosis and progressive fibrosis, necessitating novel therapeutic strategies. This study investigates the molecular mechanism by which cyclic RGD peptide (cRGD)‐modified adipose‐derived mesenchymal stem cell (ADMSC)‐derived extracellular vesicles (EVs) deliver Angiotensin‐(1–7) to attenuate NAFLD‐associated liver fibrosis. EVs were isolated from murine ADMSCs via ultracentrifugation, surface‐modified with cRGD using EDC/NHS crosslinkers, and loaded with Angiotensin‐(1–7) via an ultrasound‐assisted method. The therapeutic effects were evaluated in vitro using hepatic stellate cells (LX‐2) and in vivo using a high‐fat diet (HFD)‐induced NAFLD mouse model. Multi‐omics analyses (transcriptomics, proteomics, metabolomics) were performed on liver tissues to elucidate underlying pathways. Results demonstrated that cRGD‐modified EVs loaded with Angiotensin‐(1–7) exhibited excellent biocompatibility and targeted liver accumulation, significantly reducing hepatic lipid accumulation, fibrosis, and serum markers of liver damage (ALT, AST). Mechanistically, Angiotensin‐(1–7) activated the Mas receptor, enhancing Akt‐Foxo1‐dependent autophagy and fatty acid metabolism reprogramming, as confirmed by upregulation of autophagy‐related proteins (LC3‐II, p62) and downregulation of fibrosis markers (TGF‐β1, α‐SMA, Collagen I). Multi‐omics data revealed enrichment in fatty acid degradation and autophagy pathways, while Mas receptor inhibition abolished these effects. This study establishes that cRGD‐modified EVs deliver Angiotensin‐(1–7) as a potent strategy to mitigate NAFLD fibrosis through Mas/Akt/Foxo1 signaling, offering a promising therapeutic avenue for metabolic liver diseases.
Niu et al. (Mon,) studied this question.