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

Journal: Nature communications
Published Date: May 15, 2025

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.

Authors

  • Wenjia Liu
    2 Mechanical Engineering, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
  • Yuting Liu
    Jiangsu Key Laboratory of Crop Genetics and Physiology, Co-Innovation Center for Modern Production Technology of Grain Crops, Yangzhou University, Yangzhou, Jiangsu, China.
  • Liqiang Zhang
    Department of Radiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • Liya Li
    Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • Wenguang Yang
    School of Electromechanical and Automotive Engineering, Yantai University, Yantai, China.
  • Jia Li
    Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong, 528400, PR China; School of Pharmacy, Zunyi Medical University, Zunyi, 563000, PR China; National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
  • Wangxiao He
    Department of Medical Oncology and Department of Talent Highland, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P. R. China.

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