Single-Shot saRNA Promotes Healing After Heart Attack

Myocardial Infarction (MI) leads to the irreversible loss of cardiomyocytes and adverse remodeling, eventually progressing to heart failure (HF). Although gene- and RNA-based therapies offer promising strategies for cardiac repair, current approaches often rely on invasive intramyocardial delivery or are limited by the short duration of expression and low protein yield of traditional mRNA.

Consequently, developing a minimally invasive therapeutic platform capable of sustained expression of cardioprotective factors remains a critical unmet need in the field of cardiac therapy.

Recently, Professor Ke Cheng's team at Columbia University published a research paper titled "Single intramuscular injection of self-amplifying RNA of Nppa to treat myocardial infarction" in the prestigious international journal Science. The study developed a lipid nanoparticle-delivered self-amplifying RNA therapy (saNppa-LNP). A single intramuscular injection can achieve sustained expression of cardioprotective factors in vivo, significantly improving cardiac function and ventricular remodeling after myocardial infarction, supporting the broader potential of saRNA-LNP-based therapies for treating cardiac diseases.

Atrial Natriuretic Peptide (ANP), encoded by the Nppa gene, is a developmentally regulated cardiac hormone with potent cardioprotective functions. The research team previously observed that Nppa expression is induced following myocardial infarction in both neonatal and adult mice; however, the level of induction is significantly higher in the hearts of neonatal mice, which possess strong regenerative capabilities. This disparity suggests that elevated Nppa expression levels may be linked to enhanced cardiac regeneration, whereas the limited repair capacity of adult mouse hearts may be due to insufficient Nppa induction.

To address this, the team developed a self-amplifying RNA (saRNA) therapy delivered via lipid nanoparticles (LNPs) to drive additional Nppa expression. Unlike conventional mRNA, saRNA can self-replicate within cells, enabling more persistent protein expression at extremely low doses.

The research team reasoned that a single intramuscular injection of saRNA-LNP encoding native Nppa (saNppa-LNP) could establish an "RNA factory" in the body. This factory continuously produces and secretes Pro-ANP, a precursor that enters the circulatory system. Pro-ANP is then selectively cleaved and activated into functional ANP by Corin—a cardiac protease highly expressed only in the heart. This achieves a "muscle production, cardiac activation" model, providing long-lasting cardioprotection without the need for direct cardiac intervention.

Experimental results showed that a single intramuscular injection of saNppa-LNP in mice induced robust Pro-ANP secretion lasting for at least four weeks, outperforming an equivalent dose of mRNA-LNP. In mouse models of acute myocardial infarction and ischemia/reperfusion (I/R) injury, saNppa-LNP treatment significantly increased left ventricular ejection fraction (LVEF), reduced infarct size, and mitigated fibrosis. These therapeutic benefits were consistently validated in aged, atherosclerotic, and diabetic myocardial infarction models. Furthermore, large animal studies in a porcine I/R model confirmed that a single intramuscular injection effectively protected cardiac function and limited adverse cardiomyocyte remodeling.

Figure 1. Intramuscular injectable saNppa-LNP therapy for durable cardioprotection. (ZHANG, Kaiyue, et al., 2026)

Mechanistically, single-nucleus transcriptomic analysis (snRNA-seq) revealed that saNppa-LNP treatment reshaped the paracrine profiles of natriuretic peptide receptor-1 positive (Npr1+) endothelial and epicardial cells. This created a pro-regenerative microenvironment that promoted cardiomyocyte cell-cycle reentry and inhibited the expansion of pro-fibrotic periostin-positive (Postn+) fibroblasts. Additionally, longitudinal safety assessments showed only transient local inflammation following treatment, with no evidence of adaptive immune activation or systemic toxicity.

In conclusion, this study demonstrates that a single intramuscular injection of saNppa-LNP provides robust and lasting cardioprotection across multiple species and clinically relevant injury models. By leveraging the self-amplifying properties of saRNA and the myocardial-specific activation of Pro-ANP, this minimally invasive, single-dose therapy may offer a safe, simple, and effective strategy for cardiac repair.