exoWNT3A/RSPO1 improves HE to LPC differentiation, hepatic organoids growth, and different acute and chronic liver injuries.

Using human liver progenitor cell cultures, we showed that WNT3A and RSPO1 co-treatment could effectively regulate hepatic cell fate and uncovered their potential functional crosstalk with the PPARα signaling pathway. We also observed that dual ligands loaded on a single exosome (exoWNT3A/RSPO1) hyperactivated the WNT signaling and promoted efficient hepatic organoid growth compared to the small molecule inhibitor CHIR99021. After exoWNT3A/RSPO1 administration, we confirmed the efficient delivery and robust activation of WNT signaling in the mouse liver. Importantly, exoWNT3A/RSPO1 could accelerate liver repair and regeneration under various conditions, including acute and chronic injuries and aging-associated phenotypes.