Nucleic acid spheres for treating capillarisation of liver sinusoidal endothelial cells in liver fibrosis

IF 14.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-05-15 DOI:10.1038/s41467-025-59885-x

Wenjia Liu, Yuting Liu, Liqiang Zhang, Liya Li, Wenguang Yang, Jia Li, Wangxiao He

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Abstract

Liver sinusoidal endothelial cells (LSECs) lose their characteristic fenestrations and become capillarized during the progression of liver fibrosis. Mesenchymal stem cell (MSC) transplantation can reverse this capillarization and reduce fibrosis, but MSC therapy has practical limitations that hinder its clinical use. Here, with the help of artificial intelligence (AI), we show that MSCs secrete a microRNA (miR-325-3p) that helps restore LSEC fenestrations (tiny pores) by modulating their cytoskeleton, effectively reversing capillarization. We further develop a spherical nucleic acid (SNA) nanoparticle carrying miR-325-3p as an alternative to MSC therapy. This SNA specifically enters fibrotic LSECs via the scavenger receptor A (Scara). In three mouse models of liver fibrosis, the SNA treatment restores LSEC fenestrations, reverses capillarization, and significantly reduces fibrosis without adverse effects. Our findings highlight the potential of SNA-based therapy for liver fibrosis, paving the way for targeted nucleic acid treatments directed at LSECs and offering hope for patients.

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核酸球治疗肝纤维化肝窦内皮细胞毛细血管化

肝窦内皮细胞（LSECs）在肝纤维化的过程中失去了它们特有的开孔，并变得毛细血管化。间充质干细胞（MSC）移植可以逆转这种毛细血管化并减少纤维化，但MSC治疗具有实际局限性，阻碍了其临床应用。在这里，在人工智能（AI）的帮助下，我们发现MSCs分泌一种microRNA (miR-325-3p)，通过调节其细胞骨架，有效地逆转毛细血管化，帮助恢复LSEC开孔（微小毛孔）。我们进一步开发了一种携带miR-325-3p的球形核酸（SNA）纳米颗粒，作为MSC治疗的替代方案。这种SNA通过清扫者受体A （Scara）特异性进入纤维化LSECs。在三种肝纤维化小鼠模型中，SNA治疗恢复LSEC开窗，逆转毛细血管化，并显着减少纤维化，无不良反应。我们的研究结果强调了基于sna的肝纤维化治疗的潜力，为针对LSECs的靶向核酸治疗铺平了道路，并为患者带来了希望。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

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.