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细胞外囊泡:肝脏纤维化的新兴治疗药物

Extracellular vesicles: emerging therapeutic agents for liver fibrosis.

作者信息

Chiabotto Giulia, Semnani Armina, Ceccotti Elena, Bruno Stefania

机构信息

Department of Medical Sciences, University of Torino, Torino 10126, Italy.

Department of Applied Science and Technology, Politecnico di Torino, Turin 10129, Italy.

出版信息

Extracell Vesicles Circ Nucl Acids. 2025 May 7;6(2):216-244. doi: 10.20517/evcna.2025.08. eCollection 2025.


DOI:10.20517/evcna.2025.08
PMID:40852596
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12367467/
Abstract

Liver fibrosis is a progressive condition characterized by excessive scar tissue buildup, leading to impaired liver function and potentially cirrhosis. Despite advancements in treatment strategies, effective anti-fibrotic therapies remain an urgent unmet need. Recent research has identified extracellular vesicles (EVs) as promising therapeutic agents due to their ability to mediate intercellular communication and regulate key fibrotic pathways. This review aims to provide a comprehensive overview of the therapeutic potential of EVs in different and models of hepatic fibrosis, focusing on their natural effects and recent advancements in their engineering for enhanced efficacy. EVs can be derived from various cellular sources, including mesenchymal stromal cells (MSCs) and liver-resident cells. Biological materials, including serum, breast milk, bacteria, and plants, also serve as EV sources. Among these, MSC-EVs stand out for their therapeutic potential, which can be significantly enhanced through preconditioning with inflammatory signals, pharmacological agents, or genetic engineering to improve EV quality and efficacy. Engineering techniques have further expanded EV applications, enabling their use as precise and effective drug-delivery vehicles. Approaches such as loading EVs with pharmacological compounds, designing customized EVs, and creating EV-liposome hybrids enable targeted delivery to activated hepatic stellate cells (HSCs), central drivers of fibrosis progression. These strategies enhance the efficacy of EV-based treatments. Both natural and engineered EVs regulate critical pathways of liver fibrosis development, including activation of HSCs, modulation of pro-fibrotic genes, extracellular matrix deposition, and programmed cell death. Additionally, EVs modulate immune responses, fostering a liver microenvironment conducive to repair and regeneration. Combining the natural regenerative properties of EVs with innovative engineering strategies provides highly targeted, effective treatment approaches to restore liver function and address the urgent unmet need for chronic liver disease therapies.

摘要

肝纤维化是一种进行性疾病,其特征是瘢痕组织过度积聚,导致肝功能受损并可能发展为肝硬化。尽管治疗策略取得了进展,但有效的抗纤维化疗法仍然是迫切未满足的需求。最近的研究已将细胞外囊泡(EVs)确定为有前景的治疗剂,因为它们能够介导细胞间通讯并调节关键的纤维化途径。本综述旨在全面概述EVs在不同肝纤维化模型中的治疗潜力,重点关注其天然作用以及为提高疗效而进行工程改造的最新进展。EVs可以来源于各种细胞,包括间充质基质细胞(MSCs)和肝脏驻留细胞。生物材料,包括血清、母乳、细菌和植物,也可作为EVs的来源。其中,MSC-EVs因其治疗潜力而脱颖而出,通过用炎症信号、药物或基因工程进行预处理以提高EVs的质量和疗效,其治疗潜力可得到显著增强。工程技术进一步扩大了EVs的应用,使其能够用作精确有效的药物递送载体。诸如将药物化合物加载到EVs中、设计定制的EVs以及创建EV-脂质体杂种等方法能够将药物靶向递送至活化的肝星状细胞(HSCs),而肝星状细胞是纤维化进展的核心驱动因素。这些策略提高了基于EVs的治疗效果。天然和工程改造的EVs均调节肝纤维化发展的关键途径,包括肝星状细胞的活化、促纤维化基因的调节、细胞外基质沉积和程序性细胞死亡。此外,EVs调节免疫反应,营造有利于修复和再生的肝脏微环境。将EVs的天然再生特性与创新的工程策略相结合,可提供高度靶向、有效的治疗方法,以恢复肝功能并满足慢性肝病治疗迫切未满足的需求。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10b5/12367467/24f3009660bd/evcna-6-2-216.fig.4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10b5/12367467/1b2d6d93c650/evcna-6-2-216.fig.1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10b5/12367467/84991c94df38/evcna-6-2-216.fig.2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10b5/12367467/9f0f4f096c5e/evcna-6-2-216.fig.3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10b5/12367467/24f3009660bd/evcna-6-2-216.fig.4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10b5/12367467/1b2d6d93c650/evcna-6-2-216.fig.1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10b5/12367467/84991c94df38/evcna-6-2-216.fig.2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10b5/12367467/9f0f4f096c5e/evcna-6-2-216.fig.3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10b5/12367467/24f3009660bd/evcna-6-2-216.fig.4.jpg

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本文引用的文献

[1]
Unraveling the Exosome-miR-133a Axis: Targeting TGF-β Signaling via WJ-MSC-Derived Exosomes for Anti-Fibrotic Therapy in Liver Fibrosis.

Iran Biomed J. 2024-9-1

[2]
Platelet-rich plasma-derived extracellular vesicles improve liver cirrhosis in mice.

Regen Ther. 2024-11-6

[3]
USP9X-enriched MSC-sEV inhibits LSEC angiogenesis in MASH mice by downregulating the IκBα/NF-κB/Ang-2 pathway.

Pharmacol Res. 2024-11

[4]
ROS-responsive injectable hydrogels loaded with exosomes carrying miR-4500 reverse liver fibrosis.

Biomaterials. 2025-3

[5]
Quercetin-primed BMSC-derived extracellular vesicles ameliorate chronic liver damage through miR-136-5p and GNAS/STAT3 signaling pathways.

Int Immunopharmacol. 2024-12-5

[6]
Shaping the immune landscape: Multidimensional environmental stimuli refine macrophage polarization and foster revolutionary approaches in tissue regeneration.

Heliyon. 2024-8-30

[7]
Wharton's Jelly mesenchymal stem cell-derived extracellular vesicles induce liver fibrosis-resolving phenotype in alternatively activated macrophages.

J Cell Mol Med. 2024-9

[8]
Hemp sprout-derived exosome-like nanovesicles as hepatoprotective agents attenuate liver fibrosis.

Biomater Sci. 2024-10-8

[9]
Apoptotic vesicles (apoVs) derived from fibroblast-converted hepatocyte-like cells effectively ameliorate liver fibrosis.

J Nanobiotechnology. 2024-9-5

[10]
Mesenchymal Stromal Cell-Derived Extracellular Vesicles for Reversing Hepatic Fibrosis in 3D Liver Spheroids.

Biomedicines. 2024-8-14

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