Liu Wenjia, Liu Yuting, Zhang Liqiang, Li Liya, Yang Wenguang, Li Jia, He Wangxiao
Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Nat Commun. 2025 May 15;16(1):4517. doi: 10.1038/s41467-025-59885-x.
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.
在肝纤维化进展过程中，肝窦内皮细胞（LSECs）会失去其特有的窗孔结构并发生毛细血管化。间充质干细胞（MSC）移植可逆转这种毛细血管化并减轻纤维化，但MSC疗法存在实际局限性，阻碍了其临床应用。在此，借助人工智能（AI），我们发现MSC分泌一种微小RNA（miR-325-3p），该微小RNA通过调节LSECs的细胞骨架来帮助恢复其窗孔（小孔）结构，有效逆转毛细血管化。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疗法的替代方案。这种SNA通过清道夫受体A（Scara）特异性进入纤维化的LSECs。在三种肝纤维化小鼠模型中，SNA治疗可恢复LSECs的窗孔结构，逆转毛细血管化，并显著减轻纤维化，且无不良反应。我们的研究结果突出了基于SNA的疗法治疗肝纤维化的潜力，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。
