Disruption of the dynamic stability of the pro-inflammatory/anti-inflammatory phenotypes of macrophages within plaques significantly affects chronic vascular inflammation and exacerbates atherosclerosis. Reprogramming macrophages from a pro-inflammatory phenotype (M1) to an anti-inflammatory phenotype (M2) can slow the progression of atherosclerosis. However, chronic inflammatory stimulation can cause atherosclerotic macrophages to remain in a chromatin-closed state, inhibiting their phenotype reprogramming.
Recently, researchers published a research paper entitled "Reprogramming mitochondrial metabolism and epigenetics of macrophages via miR-10a liposomes for atherosclerosis therapy" in Nature Communications, a Nature sub-journal. This study uses miR-10a liposomes to reprogram the mitochondrial metabolism and epigenetics of macrophages for the treatment of atherosclerosis.
Atherosclerosis is a leading cause of death worldwide. It is characterized by the accumulation of lipids, immune cells, and inflammatory cytokines in the vascular intima. Macrophages retain memories of past infections and become more active when trained by endogenous atherosclerotic factors, thus promoting the progression of atherosclerosis. Evidence suggests that epigenetic reprogramming, primarily through histone modifications at the chromatin structure level, is a core mechanism supporting the enhanced function of trained innate immune cells.
Previous studies have shown that lipopolysaccharide (LPS) cannot induce an inflammatory phenotype in histone deacetylase-3 (HDAC3)-deficient macrophages, and that HDAC3 deficiency leads to a tilt towards an anti-inflammatory phenotype in macrophages. Therefore, the current poor efficacy of macrophage phenotype reprogramming therapy for atherosclerosis may be due to persistent excessive inflammatory training leading to macrophage epigenetic silencing.
M2 macrophages rely on mitochondrial oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) pathways, while M1 macrophages primarily rely on glycolysis. Impaired OXPHOS function leads to reduced acetyl-CoA supply, which may exacerbate the limitations imposed by histone deacetylases (HDACs) on macrophage epigenetic remodeling. Therefore, reprogramming mitochondrial metabolism may overcome the limitations of histone deacetylase-mediated epigenetic silencing in inflammatory macrophages and convert their phenotype to the M2 phenotype, potentially treating atherosclerosis.
The progression of atherosclerosis is regulated by hemodynamics. Stable laminar flow has an anti-atherosclerotic effect, while low shear stress or turbulent flow promotes disease development. Emerging evidence suggests that changes in blood flow conditions, both in vitro and in vivo, regulate miRNA expression. These blood flow-sensitive miRNAs, known as mechano-miRNAs, play a crucial role in the regulation of atherosclerosis. For example, previous studies have shown that the blood flow-sensitive miRNA miR-10a has a protective effect in cardiovascular disease. miR-10a can inhibit monocyte activation and restore impaired mitochondrial oxidative metabolism in M1 macrophages, thereby alleviating inflammation. Therefore, miR-10a holds promise for regulating mitochondrial energy metabolism in macrophages and macrophage-mediated atherosclerosis.
| Cat.No. | Product Name | Price |
|---|---|---|
| MIPH3016 | pEP-hsa-mir-10a | Inquiry |
| MIPHS4875 | pEZX-AM03-hsa-mir-10a | Inquiry |
| MIPHS9338 | pEZX-MR01-hsa-mir-10a | Inquiry |
| MIPRS1187 | pEZX-AM03-rno-mir-10a | Inquiry |
| MIPRS4719 | pmirGLO-rno-mir-10a | Inquiry |
| MIAHS0072 | pAdeno-hsa-miR-10a | Inquiry |
| MIAHS1584 | pLenti-III-miR-Off-hsa-miR-10a | Inquiry |
| MIARS0056 | pAdeno-rno-miR-10a-5p | Inquiry |
| MILMS2757 | pLenti-III-mir-mmu-mir-10a | Inquiry |
| MILMS3874 | pLenti-III-mir-GFP-mmu-mir-10a | Inquiry |
| MILRS0061 | pAdeno-rno-mir-10a | Inquiry |
| MILRS1998 | pLenti-III-mir-GFP-rno-mir-10a | Inquiry |
| MIMH0812 | miR-hsa-miR-10a mimics | Inquiry |
| CSC-MRH00066 | Hsa-mir-10a Overexpression Stable Cell Line | Inquiry |
| MIPHS6988 | pEZX-AM04-hsa-mir-10a | Inquiry |
However, systemic delivery of miRNAs faces numerous challenges, such as their susceptibility to rapid clearance and poor targeting of atherosclerotic plaques. In this latest study, the research team demonstrated that restoring mitochondrial respiration increases histone acetylation (AcH3) levels in atherosclerotic macrophages and improves chromatin accessibility, thereby restarting macrophage phenotypic reprogramming. The team also found that miR-10a can promote mitochondrial respiration and reorganize macrophage reprogramming.
Figure 1. Schematic diagram of the preparation of miR-10a-loaded biomimetic liposomes and reprogramming macrophage mitochondrial metabolism and epigenetic properties to treat atherosclerosis. (Fang F, et al., 2025)
To optimize delivery, prolong circulation time, and target pro-inflammatory macrophages, the team developed miR-10a@H-MNP, a liposomal nanoparticle modified with erythrocyte (RBC) membranes and hyaluronic acid (HA) to respond to reactive oxygen species (ROS) and address the challenges of systemic miRNA delivery.
These nanoparticles: 1) evade clearance by the reticuloendothelial system (RES) through the erythrocyte membrane; 2) bind to targeted activated macrophages via hyaluronic acid (HA); and 3) release miR-10a in ROS-rich plaques to reprogram the macrophage phenotype and disrupt immune training by restoring mitochondrial metabolic function and remodeling epigenetics.
The research team further demonstrated that, in a mouse model of atherosclerosis, intravenous injection of miR-10a@H-MNP specifically targets macrophages in atherosclerotic plaques, reverting them from the pro-inflammatory M1 type to the anti-inflammatory M2 type. In summary, this study develops a therapeutic strategy to halt the progression of atherosclerosis through precise regulation of mitochondrial metabolism, with significant clinical application potential.
Reference
Fang F, et al. Reprogramming mitochondrial metabolism and epigenetics of macrophages via miR-10a liposomes for atherosclerosis therapy. Nature Communications, 2025, 16(1): 9117.