Hepatic Stellate Cell- and Liver Microbiome-Specific Delivery System for Dihydrotanshinone I to Ameliorate Liver Fibrosis

Liver fibrosis is a major contributor to the morbidity and mortality associated with liver diseases, yet effective treatment options remain limited. Hepatic stellate cells (HSCs) are a promising target for hepatic fibrogenesis due to their pivotal role in disease progression. Our previous research has demonstrated the potential of Dihydrotanshinone I (DHI), a lipophilic component derived from the natural herb Salvia miltiorrhiza Bunge, in treating liver fibrosis by inhibiting the YAP/TEAD2 interaction in HSCs. However, the clinical application of DHI faces challenges due to its poor aqueous solubility and lack of specificity for HSCs. Additionally, recent studies have implicated the impact of liver microbiota, distinct from gut microbiota, on the pathogenesis of liver diseases. In this study, we have developed an HSC- and microbiome-specific delivery system for DHI by conjugating prebiotic-like cyclodextrin (CD) with vitamin A, utilizing PEG2000 as a linker (VAP2000@CD). Our results demonstrate that VAP2000@CD markedly enhances the cellular uptake in human HSC line LX-2 and enhances the deposition of DHI in the fibrotic liver in vivo. Subsequently, intervention with DHI-VAP2000@CD has shown a notable reduction in bile duct-like structure proliferation, collagen accumulation, and the expression of fibrogenesis-associated genes in rats subjected to bile duct ligation. These effects may be attributed to the regulation of the YAP/TEAD2 interaction. Importantly, the DHI-VAP2000@CD intervention has also restored microbial homeostasis in the liver, promoting the amelioration of liver inflammation. Overall, our findings indicate that DHI-VAP2000@CD represents a promising therapeutic approach for liver fibrosis by specifically targeting HSCs and restoring the liver microbial balance.