{"title":"Dual-ligand engineered exosome regulates WNT signaling activation to promote liver repair and regeneration.","authors":"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,Yun-Shen Chan","doi":"10.1038/s41467-025-64069-8","DOIUrl":null,"url":null,"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.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"88 1","pages":"9019"},"PeriodicalIF":15.7000,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Communications","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1038/s41467-025-64069-8","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.