Dual-ligand engineered exosome regulates WNT signaling activation to promote liver repair and regeneration

Lingyan Yang, Shixiang Wang, Zhiping Qiao, Yue Liu, Xu Wang, Liying Liu, Chunfang Yang, Jiying Ding, Miao Lei, Jiayi Zheng, Wenxiang Hu, Ye-guang Chen and Yun-Shen Chan ()
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Lingyan Yang: Guangzhou International Bio Island
Shixiang Wang: Guangzhou International Bio Island
Zhiping Qiao: Guangzhou International Bio Island
Yue Liu: Guangzhou International Bio Island
Xu Wang: Guangzhou International Bio Island
Liying Liu: Guangzhou International Bio Island
Chunfang Yang: Guangzhou International Bio Island
Jiying Ding: Guangzhou International Bio Island
Miao Lei: Guangzhou International Bio Island
Jiayi Zheng: Guangzhou International Bio Island
Wenxiang Hu: Guangzhou International Bio Island
Ye-guang Chen: Guangzhou International Bio Island
Yun-Shen Chan: Guangzhou International Bio Island

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract WNT signaling is an essential pathway regulating tissue morphogenesis and regeneration. However, harnessing the pathway for regenerative medicine has been challenging due to the lack of approaches to identify and deliver specific WNT ligands to the target tissue. Herein, we reported that WNT and R-spondin (RSPO) proteins could be transported on engineered exosomes and activate the pathway synergistically. We showed that WNT3A and RSPO1 co-treatment could effectively regulate hepatic cell fate and uncovered functional crosstalk with the PPARα signaling pathway. Moreover, dual-ligand-carrying exosome (exoWNT3A/RSPO1) hyperactivated the WNT signaling and promoted efficient hepatic organoid growth compared to the small molecule inhibitor CHIR99021. Importantly, the exosome can be efficiently delivered for robust WNT signaling activation in the liver. Remarkably, exoWNT3A/RSPO1 could accelerate liver repair and regeneration under various conditions, including acute and chronic injuries and aging-associated phenotypes. Collectively, our work revealed the broad therapeutic effects of WNT signaling activation in the liver through the dual-ligand-carrying exosomes.

Date: 2025
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DOI: 10.1038/s41467-025-64069-8

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