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一种基于外泌体的“吃我/别吃我”联合策略用于急性肝损伤治疗。

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

作者信息

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

机构信息

Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.

出版信息

Cell Rep Med. 2025 Apr 15;6(4):102033. doi: 10.1016/j.xcrm.2025.102033. Epub 2025 Mar 21.

DOI:10.1016/j.xcrm.2025.102033
PMID:40120577
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12047510/
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 (designated Wnt2@Exo). In both acetaminophen (APAP) and dimethylnitrosamine (DMN)-induced murine liver injury models, RLTR-Wnt2@Exo demonstrates LSEC-specific targeting and significant hepatoprotection. This engineered exosome platform provides a therapeutic strategy for DILI.

摘要

药物性肝损伤（DILI）涉及多方面的发病机制，需要有效的治疗策略。肝窦内皮细胞（LSEC）分泌的Wnt2可激活Wnt/β-连环蛋白信号通路，以促进损伤后肝细胞的增殖。为应对靶向递送和逃避吞噬这两个双重挑战，我们开发了一种组合的“吃我/别吃我”策略。通过将DMPE-PEG2000-CRLTRKRGLK插入源自bEnd.3细胞的外泌体脂质膜中，构建了RLTRKRGLK（RLTR）肽功能化的外泌体。表面展示的RLTR介导外泌体在LSEC中富集，而CD47工程改造通过“别吃我”信号减少巨噬细胞清除。然后，慢病毒转染可将功能性Wnt2 mRNA稳定封装到外泌体中（命名为Wnt2@Exo）。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@Exo均表现出对LSEC的特异性靶向作用和显著的肝保护作用。这种工程化的外泌体平台为DILI提供了一种治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e5b/12047510/2a34e8db2ac9/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e5b/12047510/ddcb4c7f677e/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e5b/12047510/5c8eaad873ba/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e5b/12047510/5b1905d6a9d1/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e5b/12047510/bcc02904783c/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e5b/12047510/122d71ec8c6a/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e5b/12047510/2e157069e16b/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e5b/12047510/2a34e8db2ac9/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e5b/12047510/ddcb4c7f677e/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e5b/12047510/5c8eaad873ba/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e5b/12047510/5b1905d6a9d1/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e5b/12047510/bcc02904783c/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e5b/12047510/122d71ec8c6a/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e5b/12047510/2e157069e16b/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e5b/12047510/2a34e8db2ac9/gr6.jpg

相似文献

[1]
A combined "eat me/don't eat me" strategy based on exosome for acute liver injury treatment.

Cell Rep Med. 2025-4-15

[2]
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[3]
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[4]
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[5]
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[6]
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[8]
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[9]
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[10]
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引用本文的文献

[1]
CAR-exosomes derived from immune cells: an emerging nanoscale vanguard in overcoming tumor immunotherapy hurdles.

Front Immunol. 2025-8-19

[2]
Engineered Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Mitigate Liver Fibrosis by Delivering USP10 to Reprogram Macrophage Phenotype.

Biomater Res. 2025-8-26

本文引用的文献

[1]
The antitumor activities of anti-CD47 antibodies require Fc-FcγR interactions.

Cancer Cell. 2023-12-11

[2]
Engineering strategies and optimized delivery of exosomes for theranostic application in nerve tissue.

Theranostics. 2023

[3]
Engineered exosomes from different sources for cancer-targeted therapy.

Signal Transduct Target Ther. 2023-3-15

[4]
The evolving role of liver sinusoidal endothelial cells in liver health and disease.

Hepatology. 2023-8-1

[5]
Neuronal signal-regulatory protein alpha drives microglial phagocytosis by limiting microglial interaction with CD47 in the retina.

Immunity. 2022-12-13

[6]
Bone-targeting delivery of platelet lysate exosomes ameliorates glucocorticoid-induced osteoporosis by enhancing bone-vessel coupling.

J Nanobiotechnology. 2022-10-31

[7]
Single-cell spatial transcriptomics reveals a dynamic control of metabolic zonation and liver regeneration by endothelial cell Wnt2 and Wnt9b.

Cell Rep Med. 2022-10-18

[8]
The Crosstalk Between Liver Sinusoidal Endothelial Cells and Hepatic Microenvironment in NASH Related Liver Fibrosis.

Front Immunol. 2022

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Modification of adipose mesenchymal stem cells-derived small extracellular vesicles with fibrin-targeting peptide CREKA for enhanced bone repair.

Bioact Mater. 2022-5-31

[10]
Liver Endothelial Heg Regulates Vascular/Biliary Network Patterning and Metabolic Zonation Via Wnt Signaling.

Cell Mol Gastroenterol Hepatol. 2022

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