In a groundbreaking advance that could transform the landscape of cardiovascular disease treatment, researchers have unveiled a novel therapeutic strategy that manipulates mitochondrial metabolism and epigenetic regulation in macrophages to combat atherosclerosis. Utilizing miR-10a-loaded liposomes, the study published in Nature Communications reveals a sophisticated approach to reprogram immune cell function, shedding light on the intricate interplay between cellular metabolism, epigenetic modifications, and chronic vascular inflammation.
Atherosclerosis remains a leading cause of morbidity and mortality worldwide, largely driven by the accumulation of lipid-laden macrophages, known as foam cells, within arterial walls. These transformed macrophages contribute to plaque formation, instability, and eventual cardiovascular events. Central to this pathological process is the reprogramming of macrophage metabolism and gene expression, which has spurred intensive research efforts aimed at identifying molecular interventions capable of restoring cellular homeostasis and attenuating inflammatory damage.
The crux of the new study lies in the targeted delivery of microRNA-10a (miR-10a) encapsulated in liposomes, which specifically modulate the metabolic machinery and epigenetic regulators of macrophages implicated in atherosclerotic progression. MicroRNAs, small non-coding RNA molecules, play pivotal roles in post-transcriptional gene silencing and have emerged as potent modulators of immune cell phenotype. By harnessing miR-10a’s regulatory potential, the researchers sought to shift the metabolic state of macrophages from a pro-inflammatory to a reparative, anti-atherogenic profile.
Mitochondrial metabolism is increasingly recognized as a central node in immune cell programming, influencing not only energy production but also the generation of signaling metabolites that dictate epigenetic landscapes. In the context of macrophages, a shift towards oxidative phosphorylation and enhanced mitochondrial function correlates with resolution of inflammation, whereas glycolytic reprogramming promotes sustained pro-inflammatory states. The study demonstrates that miR-10a liposomes restore mitochondrial integrity and bioenergetic capacity, leading to marked reductions in inflammatory cytokine expression and foam cell formation.
Crucially, the therapeutic efficacy of miR-10a was linked to its impact on epigenetic regulators, specifically histone-modifying enzymes that control chromatin accessibility and gene transcription patterns. Through downregulation of key histone deacetylases and methyltransferases, miR-10a facilitated the reactivation of genes involved in lipid metabolism and anti-inflammatory responses. This dual action on mitochondrial function and epigenetic control represents a synergistic mechanism that efficiently reprograms macrophages, attenuating the pathogenic cycle that underpins atherosclerosis.
Liposomes served as a highly effective delivery vehicle, overcoming previous barriers related to stability, cellular uptake, and targeted tissue distribution of RNA therapeutics. Their nanoscale size and biocompatibility enabled precise delivery of miR-10a to macrophages within the atherosclerotic plaque microenvironment. Upon administration in murine models of atherosclerosis, miR-10a liposomes significantly reduced plaque burden and improved arterial function, providing compelling in vivo validation of this strategy.
Beyond plaque regression, the treatment also enhanced systemic metabolic profiles, as evident by improved lipid panels and reduced markers of systemic inflammation. This suggests that metabolic reprogramming of macrophages not only impacts local disease processes but may also confer broader cardiovascular benefits. The findings highlight the interconnectedness of immune cell metabolism and systemic homeostasis, expanding the therapeutic potential of miRNA-based interventions.
This study further contributes to the burgeoning field of immunometabolism, where the metabolic state of immune cells is increasingly appreciated as a determinant of their function and fate. By delineating the precise molecular targets of miR-10a and elucidating its epigenetic effects, the research adds valuable insight to the mechanistic underpinnings that govern macrophage plasticity in chronic inflammatory diseases.
The implications for clinical translation are profound. Current atherosclerosis treatments primarily focus on lipid-lowering therapies and symptomatic management, with limited options for directly modulating inflammatory processes at the cellular level. miRNA-based therapeutics, especially those leveraging advanced delivery systems like liposomes, open new frontiers for precision medicine aimed at reprogramming disease-driving immune cells rather than merely suppressing symptoms.
Nevertheless, several challenges remain before this innovative approach can be brought to the clinic. Long-term safety, dosing regimens, and the potential for off-target effects require meticulous evaluation in preclinical and clinical studies. Moreover, the heterogeneity of macrophage populations and their dynamic roles in various stages of atherosclerosis necessitate careful optimization of treatment timing and combinations with existing therapies.
As the study’s first authors underscore, future directions include investigating the combinatorial effects of miR-10a with other metabolic and epigenetic modulators, as well as extending this strategy to other chronic inflammatory and metabolic conditions. The versatility of miRNA therapeutics encoded within liposomes holds promise to revolutionize a spectrum of diseases where immune cell dysfunction is a key driver.
This research epitomizes the power of interdisciplinary collaboration, marrying molecular biology, nanotechnology, immunology, and metabolism to tackle one of the most pressing public health challenges. It underscores the paradigm shift from traditional pharmacology toward sophisticated gene regulatory therapies tailored to the cellular microenvironment and metabolic state.
In summary, the exploitation of miR-10a-loaded liposomes to reprogram mitochondrial metabolism and epigenetic architecture of macrophages marks a transformative advancement in cardiovascular disease therapy. By correcting the root cause of immune dysregulation in atherosclerosis, this approach offers hope for durable, targeted interventions that move beyond symptom control to fundamentally alter disease trajectory.
The exciting convergence of miRNA biology and lipid nanocarrier technology detailed in this study sets the stage for a new era of smart therapeutics that harness endogenous regulatory circuits to restore health. With further refinement and clinical validation, miR-10a liposomal therapy could become a cornerstone in the fight against atherosclerosis, heralding a future where precision epigenetic reprogramming becomes a standard weapon against chronic inflammation.
As researchers continue to decode the complex crosstalk between metabolism and gene expression in immune cells, miRNA-based interventions exemplify the next-generation tools capable of exploiting this nexus. The promise of this innovative treatment lies not only in its therapeutic efficacy but also in its potential to inspire new lines of inquiry into the metabolic-epigenetic interface across multiple disease domains.
Ultimately, this pioneering work reaffirms the shifting paradigm in biomedical research, where the integration of molecular insights and nanomedicine offers unprecedented opportunities to tackle the root causes of disease at a cellular and epigenetic level. The remarkable efficacy of miR-10a liposomes in modulating macrophage function could pave the way for entirely new classes of therapies designed to re-educate the immune system and restore tissue homeostasis.
With cardiovascular disease continuing to impose a staggering global health burden, advances such as these propel us closer to groundbreaking therapies that blend molecular precision with innovative delivery platforms. This study not only showcases the transformative potential of miRNA therapeutics but also exemplifies the future trajectory of personalized medicine aimed at correcting metabolic and epigenetic aberrancies at their source.
Article References:
Fang, F., Wang, E., Yang, H. et al. Reprogramming mitochondrial metabolism and epigenetics of macrophages via miR-10a liposomes for atherosclerosis therapy. Nat Commun 16, 9117 (2025). https://doi.org/10.1038/s41467-025-64201-8
Tags: cardiovascular disease treatment advancementschronic vascular inflammation treatmentepigenetic regulation of immune cellsimmune cell metabolism modulationlipid-laden macrophages and foam cellsmacrophage reprogramming for atherosclerosismicroRNA in gene expression regulationmiR-10a liposomes therapymitochondrial metabolism in cardiovascular diseasenovel strategies for atherosclerosis managementtargeted delivery of microRNAtherapeutic interventions for inflammatory damage
