Vitamin A-coupled MSCs- derived extracellular vesicles relieve acute liver injury by targeting hepatic stellate cells to deliver REDD1.

Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) offer great potential for treating liver injury. However, owing to their intrinsic surface characteristics, bare EVs are non-specifically distributed in the liver tissue after systemic administration, leading to limited therapeutic efficacy. Acute liver injury, often induced by acetaminophen overdose, can progress to life-threatening fibrosis, with hepatic stellate cells (HSCs) recognized as central drivers of this pathological process. While regulated in development and DNA damage response 1 (REDD1) has demonstrated antifibrotic effects by inhibiting HSCs activation, its clinical application has been hindered by challenges in targeted delivery. Utilizing the natural affinity of vitamin A (VA) for retinol binding protein receptors on HSCs, this study addresses the critical need for targeted therapies in acute liver injury by developing a novel delivery system based on VA-conjugated EVs (V-EVs) to transport the therapeutic gene REDD1 specifically to activated HSCs (aHSCs). After loading with REDD1 (V-EVREDD1), the system showed enhanced cellular uptake in activated HSCs in vitro and effective hepatic accumulation in vivo. Treatment with V-EVREDD1 significantly suppressed HSCs activation, reduced inflammation and hepatocyte apoptosis, improved liver function, and alleviated liver fibrosis in experimental models. This work highlights a promising strategy that combines targeted vesicle delivery with gene therapy, offering a potential avenue for improving the precision and efficacy of treatments for liver injury and fibrosis.