Reprogramming mitochondrial metabolism and epigenetics of macrophages via miR-10a liposomes for atherosclerosis therapy

Fei Fang, Erxiang Wang, Hanqiao Yang, Ting Zhao, Qiwei Wang, Zhen Zhang, Yang Song and Xiaoheng Liu ()
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Fei Fang: Sichuan University
Erxiang Wang: Sichuan University
Hanqiao Yang: Sichuan University
Ting Zhao: Sichuan University
Qiwei Wang: Sichuan University
Zhen Zhang: Affiliated Hospital of Southwest Jiaotong University
Yang Song: Sichuan University
Xiaoheng Liu: Sichuan University

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

Abstract: Abstract Disruption in the dynamic stability of macrophage pro/anti-inflammatory phenotypes within plaques significantly impacts chronic vascular inflammation and exacerbates atherosclerosis. Reprogramming macrophages from pro-inflammatory to anti-inflammatory phenotype mitigates atherosclerosis progression. However, chronic inflammatory stimulation induces a closed chromatin state in atherosclerotic macrophages, inhibiting their phenotype reprogramming. This study demonstrates that restoring mitochondrial respiration increases histone acetylation (AcH3) and enhances chromatin accessibility in atherosclerotic macrophages, restarting macrophage phenotype reprogramming. Additionally, we identified that miR-10a can facilitate mitochondrial respiration and reorganize macrophage reprogramming. To optimize delivery, prolong circulation time, and target pro-inflammatory macrophages, we developed red blood cell membrane-modified liposome nanoparticles (miR-10a@H-MNP) to deliver miR-10a. Hyaluronic acid was conjugated to the liposomes to specifically target pro-inflammatory macrophages in plaque. Intravenous administration of miR-10a@H-MNP significantly alleviated atherosclerosis progression in male mice. Thus, the epigenomic priming approach developed here effectively triggers macrophage reprogramming in atherosclerosis, presenting a promising metabolically based epigenetic modulation method for plaque clearance.

Date: 2025
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DOI: 10.1038/s41467-025-64201-8

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