MSC-derived apoptotic vesicles remodel hepatic macrophage polarization and suppress fibrosis via miR-6869-5p-mediated inhibition of FGF1 and HMGB1.

Chronic liver fibrosis remains a major healthcare burden with no approved pharmacotherapies currently available that directly target the fibrotic process. Although apoptotic vesicles (apoVs) derived from human umbilical cord mesenchymal stem cells (hUMSCs) hold great therapeutic potential for tissue repair, their mechanisms in alleviating liver fibrosis and their feasibility as siRNA carriers remain unclear. Here, we demonstrate that systemically administered apoVs exhibit robust liver tropism, efficiently delivering miR-6869-5p to both hepatic stellate cells (HSCs) and macrophages. Mechanistically, miR-6869-5p directly targets fibroblast growth factor 1 (FGF1) to suppress the PI3K/AKT/mTOR signaling pathway, thereby inhibiting HSC activation and reducing collagen deposition. Simultaneously, it targets high-mobility group box 1 (HMGB1) to attenuate NF-κB activity and establish an antifibrotic microenvironment through HSC-macrophage crosstalk. In clinical cohorts (n = 100), serum miR-6869 - 5p levels were inversely correlated with fibrosis indices. Leveraging these unique properties, we engineered apoVs loaded with antifibrotic TANGO1 siRNA (si-apoVs), which blocks collagen secretion; this achieves enhanced antifibrotic efficacy in CCl₄-induced liver fibrosis models while mitigating the pro-inflammatory side effects associated with free siRNA. This study identifies hUMSC-derived apoVs as a liver-targeted, dual-action therapeutic platform, and si-apoVs represent a potent, translation-ready strategy for the treatment of liver fibrosis.