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

Wenjia Liu (), Yuting Liu, Liqiang Zhang, Liya Li, Wenguang Yang, Jia Li and Wangxiao He ()
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Wenjia Liu: The Second Affiliated Hospital of Xi’an Jiaotong University
Yuting Liu: The Second Affiliated Hospital of Xi’an Jiaotong University
Liqiang Zhang: The Second Affiliated Hospital of Xi’an Jiaotong University
Liya Li: The Second Affiliated Hospital of Xi’an Jiaotong University
Wenguang Yang: The First Affiliated Hospital of Xi’an Jiaotong University
Jia Li: The Second Affiliated Hospital of Xi’an Jiaotong University
Wangxiao He: The First Affiliated Hospital of Xi’an Jiaotong University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59885-x

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