Quercetin Delivered by Mesenchymal Stem Cell-Derived Exosomes Improves Liver Fibrosis via the PI3K/Akt Signaling...

Liver fibrosis represents a critical stage in the progression of chronic liver diseases to cirrhosis and hepatocellular carcinoma; however, effective therapeutic options remain limited. Although quercetin, a natural flavonol, possesses potent antifibrotic properties, its clinical utility is severely hindered by poor aqueous solubility and low bioavailability. To address this limitation, we developed a nanoparticle-based drug delivery system using quercetin-loaded human umbilical cord mesenchymal stem cell (hUC-MSC)-derived exosomes (hUC-MSC-exo-Que). Leveraging the innate biocompatibility and targeting capability of exosomes, this strategy aims to improve the pharmacokinetic limitations of quercetin and amplify its therapeutic efficacy. Our results demonstrate that hUC-MSC-exo-Que significantly attenuates liver fibrosis in a carbon tetrachloride-induced mouse model, outperforming free quercetin at the equivalent dose. This enhanced efficacy is attributed to the superior inhibition of hepatic stellate cell activation, as confirmed by in vitro studies. The engineered exosomes exhibited a sustained drug release profile (up to 48 h) and maintained excellent stability for at least 1 week. Integrating network pharmacology with experimental validation, we identify the antifibrotic mechanism involving potent inhibition of the PI3K/Akt signaling pathway, with hUC-MSC-exo-Que achieving markedly greater pathway suppression than free quercetin. By successfully transforming a potent but poorly bioavailable phytochemical into a targeted nanotherapeutic, we present a promising preclinical strategy for liver fibrosis treatment and demonstrate a proof-of-concept platform for hydrophobic drug delivery.