Beyond the paradox: Cardiac-specific miR-106a delivery as a translational turning point for heart failure?

Heart failure (HF) remains a global health burden and a leading cause of death and disability. In Asia, HF prevalence is projected to reach 74.5 million by 2050, a 127.6% increase from 2025,¹ driven by rising cardiometabolic disease across the region. While current therapies target haemodynamic impairment and pathological neurohormonal hyperactivation, they offer limited benefit against progressive myocardial decline and cardiovascular mortality. Novel therapeutics are urgently needed to overcome challenges of poor tissue specificity, limited intracellular delivery and suboptimal pharmacokinetics.

MicroRNAs (miRNAs) are small non-coding RNAs, typically 20–24 nucleotides long, that regulate key post-transcriptional gene expression by binding to complementary sequences in messenger RNAs (mRNAs), leading to mRNA degradation or inhibition of translation. MiRNAs have recently emerged as promising biomarkers and potential therapeutic targets in HF. Their clinical translation, however, hinges on precise delivery to minimize off-target effects and enhancing biodistribution. In this context, Lu et al. recently reported a cardiac targeting peptide (CTP; 12-amino acid sequence APWHLSSQYSRT) conjugated to miR-106a (CTP–miR-106a), which reversed cardiac hypertrophy and dysfunction in an angiotensin II/isoproterenol-induced mouse model of HF.² This study builds on prior in vitro evidence demonstrating that CTP–miR-106a selectively attenuates phenylephrine- and angiotensin II-induced cardiomyocyte hypertrophy, with preferential uptake over the human embryonic kidney 293 cell line, cardiac fibroblasts and endothelial cells.³

Following intravenous administration of 10 mg/kg of the dual-reporter construct Cy5.5–CTP–miR-106a–Cy3, which is linked via a disulphide bond cleavable by endogenous reductases to release Cy5.5–CTP and miR-106a–Cy3, cardiac expression of miR-106a peaked at 30 min post-injection.² This was accompanied by tissue-level expression of the miR-106a–Cy3 reporter. The Cy5.5–CTP moiety was subsequently expelled from the myocardium within 3.5 h and cleared via hepatic and renal pathways. In contrast, miR-106a–Cy3 remained upregulated in cardiac tissue at 3.5 h, and elevated miR-106a mRNA levels persisted up to 7 days. Importantly, neither miR-106a–Cy3 nor miR-106a gene expression was detected in the liver, kidney or lung, suggesting cardiac-specific uptake. However, this observation contrasts with earlier studies by the same group, in which mice injected with 10 mg/kg of Cy5.5–CTP alone (without miR-106a moiety) exhibited robust and peak uptake in the liver and kidney as early as 15 min post-injection.⁴ This uptake paralleled the observations in the heart but declined more slowly, indicating delayed clearance.

Despite these findings, the precise mechanisms underlying CTP's cardiac specificity remain unclear. It is unknown whether uptake occurs via a dedicated membrane receptor or through receptor-independent transduction and endocytosis pathways.⁵ Similarly, the mechanism responsible for the subsequent expulsion of the CTP moiety from cardiomyocytes is not well understood. Preliminary findings suggest that the potassium voltage-gated channel KCNH5 may be involved in CTP transduction and uptake⁴; however, definitive evidence from cardiomyocyte-specific knock-out or non-cardiomyocyte knock-in models are lacking. Notably, the same group reported minimal toxicity following a single dose of CTP. No significant effects were observed on key ion channels responsible for electrical conduction in cardiomyocytes in vitro, nor were there any overt adverse effects on haematological and blood chemistry parameters, blood pressure or magnetic resonance imaging-based cardiac function.⁶ Collectively, these findings support a favourable safety profile for the CTP delivery system.

While this novel therapeutic delivery system suggests a promising cardiac-targeted application of miR-106a for HF, these findings contrast with earlier studies demonstrating pathogenic roles of miR-106a in cardiac disease. Guan et al. reported that miR-106a contributes to cardiac hypertrophy in a transverse aortic constriction model of pressure overload in mice, as well as in angiotensin II-treated cardiomyocytes. This effect was mediated through direct targeting of mitofusin 2, thereby modulating mitochondrial dynamics by impairing the fusion process.⁷ Similarly, Hao et al. identified a pathogenic role of endogenous miR-106a upregulation in myocardial ischemia/reperfusion injury, which could be attenuated by the long non-coding RNA FGD5-AS1 via activation of SMAD5.⁸ The reasons underlying the apparent complexity and conflicting roles of miR-106a across studies remain unclear. Potential contributing factors include differences in bioavailability among delivery systems, cell- versus organ-specific targeting, endogenous expression versus exogenous administration of miR-106a, and the pathological distinctions between cardiac disease models. Further investigations using both miR-106a mimics and inhibitors are warranted to elucidate these pleiotropic effects and to clarify its therapeutic potential (Figure 1).

In patients with acute HF, plasma levels of miR-106a have been reported to be downregulated, exhibiting negative correlations with NT-proBNP and hs-CRP levels, which are two well-established biomarkers of HF severity.^{9, 10} This inverse relationship suggests a potential protective role of miR-106a in modulating hemodynamic stress and inflammation, thereby supporting the rationale for exogenous restoration as a therapeutic strategy. However, conflicting evidence exists: upregulation of miR-106a has also been reported in the serum of patients with acute myocardial infarction,⁸ challenging the therapeutic premise of supplementation in the context of impaired cardiac function and subsequent HF. Beyond cardiovascular disease, miR-106a is frequently dysregulated across a spectrum of malignancies and non-cancer pathologies,¹¹ with evidence supporting both tumour-suppressive and oncogenic roles. These inconsistencies, both in miR-106 expression patterns and detection methodologies, even within studies of the same disease, complicate its clinical translation. Given its inclusion in the proto-oncogenic miR-106a-363 cluster, the potential for oncogenic activation following chronic overexpression or sustained cardiac delivery of miR-106a warrants careful investigation. Addressing this risk is essential before advancing miR-106a-based therapies towards clinical application.

It is increasingly evident that miRNAs play a crucial role in regulating cardiac hypertrophy and failure development, yet the mechanistic underpinnings and translational potential for such targeted therapy remain incompletely understood. Advances in deep RNA sequencing and bioinformatics have significantly expanded our ability to profile miRNA landscapes in detail and infer functional networks in HF. As more direct mRNA targets of miRNAs are experimentally validated, systems-level pathway analysis will be critical to unravel the complex and context-dependent roles of miRNAs in cardiac remodelling. In this light, miR-106a exemplifies a paradox: its downregulation in acute HF suggests a protective role against hemodynamic stress and inflammation, while its upregulation in myocardial infarction and potential oncogenic activity within the miR-106a∼363 cluster raises concerns about unintended consequences of therapeutic restoration. Resolving this duality—between hypertrophic regression and proliferative risk—will require integrative studies that span cardiac, inflammatory and oncogenic signalling axes, before miR-106a-based interventions can be safely introduced into the clinic.

W.-W.L. conceptualized, visualized, wrote and edited the manuscript.

The author declares that he has no known competing commercial interests or personal relationships that could have influenced the work reported here.

Ethics approval and informed consent are not applicable to this article as the commentary was conducted based on available publications.