A combined "eat me/don't eat me" strategy based on exosome for acute liver injury treatment.

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-04-15 Epub Date: 2025-03-21 DOI:10.1016/j.xcrm.2025.102033

Wei Du, Chen Chen, YingYing Liu, Huiyi Quan, Ming Xu, JingJing Liu, Ping Song, ZhiQiang Fang, ZhenSheng Yue, Hao Xu, YuWei Ling, JuanLi Duan, Fei He, Lin Wang

{"title":"A combined \"eat me/don't eat me\" strategy based on exosome for acute liver injury treatment.","authors":"Wei Du, Chen Chen, YingYing Liu, Huiyi Quan, Ming Xu, JingJing Liu, Ping Song, ZhiQiang Fang, ZhenSheng Yue, Hao Xu, YuWei Ling, JuanLi Duan, Fei He, Lin Wang","doi":"10.1016/j.xcrm.2025.102033","DOIUrl":null,"url":null,"abstract":"Drug-induced liver injury (DILI) involves multifaceted pathogenesis, necessitating effective therapeutic strategies. Wnt2, secreted by liver sinusoidal endothelial cell (LSEC), activates the Wnt/β-catenin signaling pathway to promote hepatocyte proliferation after injury. To address the dual challenges of targeted delivery and phagocytosis evasion, we develop a combined \"eat me/don't eat me\" strategy. RLTRKRGLK (RLTR) peptide-functionalized exosomes are engineered by inserting DMPE-PEG2000-CRLTRKRGLK into the lipid membrane of exosome derived from bEnd.3 cell. Surface-displayed RLTR mediates exosomal enrichment in LSEC, while CD47 engineering reduces macrophage clearance via \"don't eat me\" signaling. Then, lentiviral transfection enables stable encapsulation of functional Wnt2 mRNA into ExoCD47 (designated Wnt2@ExoCD47). In both acetaminophen (APAP) and dimethylnitrosamine (DMN)-induced murine liver injury models, RLTR-Wnt2@ExoCD47 demonstrates LSEC-specific targeting and significant hepatoprotection. This engineered exosome platform provides a therapeutic strategy for DILI.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102033"},"PeriodicalIF":11.7000,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12047510/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Reports Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.xcrm.2025.102033","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/3/21 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Drug-induced liver injury (DILI) involves multifaceted pathogenesis, necessitating effective therapeutic strategies. Wnt2, secreted by liver sinusoidal endothelial cell (LSEC), activates the Wnt/β-catenin signaling pathway to promote hepatocyte proliferation after injury. To address the dual challenges of targeted delivery and phagocytosis evasion, we develop a combined "eat me/don't eat me" strategy. RLTRKRGLK (RLTR) peptide-functionalized exosomes are engineered by inserting DMPE-PEG2000-CRLTRKRGLK into the lipid membrane of exosome derived from bEnd.3 cell. Surface-displayed RLTR mediates exosomal enrichment in LSEC, while CD47 engineering reduces macrophage clearance via "don't eat me" signaling. Then, lentiviral transfection enables stable encapsulation of functional Wnt2 mRNA into Exo^CD47 (designated Wnt2@Exo^CD47). In both acetaminophen (APAP) and dimethylnitrosamine (DMN)-induced murine liver injury models, RLTR-Wnt2@Exo^CD47 demonstrates LSEC-specific targeting and significant hepatoprotection. This engineered exosome platform provides a therapeutic strategy for DILI.

查看原文本刊更多论文

基于外泌体的联合“吃我/不吃我”策略治疗急性肝损伤。

药物性肝损伤的发病机制是多方面的，需要有效的治疗策略。肝窦内皮细胞（liver sinusoidal endothelial cell， LSEC）分泌Wnt2，激活Wnt/β-catenin信号通路，促进损伤后肝细胞增殖。为了应对靶向给药和逃避吞噬的双重挑战，我们制定了一项“吃我/不吃我”的联合策略。RLTRKRGLK （RLTR）肽功能化外泌体是通过将DMPE-PEG2000-CRLTRKRGLK插入到源自bEnd的外泌体的脂质膜中来设计的。3细胞。在LSEC中，表面显示的RLTR介导外泌体富集，而CD47工程通过“不要吃我”信号减少巨噬细胞的清除。然后，慢病毒转染可以将功能性Wnt2 mRNA稳定地封装到ExoCD47中（指定为Wnt2@ExoCD47）。在对乙酰氨基酚（APAP）和二甲基亚硝胺（DMN）诱导的小鼠肝损伤模型中，RLTR-Wnt2@ExoCD47均显示lsec特异性靶向和显著的肝保护作用。这种工程外泌体平台为DILI提供了一种治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.