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Single intramuscular injection of self-amplifying RNA of Nppa to treat myocardial infarction.

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Title: Single intramuscular injection of self-amplifying RNA of Nppa to treat myocardial infarction.
Authors: Zhang, Kaiyue (AUTHOR), Tao, Hongyan (AUTHOR), Zhu, Dashuai (AUTHOR), Yue, Zhang (AUTHOR), Hu, Shiqi (AUTHOR), Wu, Yiping (AUTHOR), Yan, Na (AUTHOR), Hu, Yilan (AUTHOR), Liu, Shuo (AUTHOR), Liu, Mengrui (AUTHOR), Vahl, Torsten Peter (AUTHOR), Ranard, Lauren Sharan (AUTHOR), Cheng, Xiao (AUTHOR), Romanov, Alexander (AUTHOR), Liu, Jiaming (AUTHOR), Zhang, Savannah Weihang (AUTHOR), Li, Yuan (AUTHOR), Lu, Chao (AUTHOR), Shen, Ming (AUTHOR), Lewis, Andrew (AUTHOR)
Source: Science. 3/5/2026, Vol. 391 Issue 6789, p1-14. 14p.
Subjects: Intramuscular injections, Myocardial infarction, Atrial natriuretic peptides, Cardiac regeneration, Cardiotonic agents, Natriuretic peptides, Nucleic acid amplification techniques, Liposomes
Abstract: Self-amplifying RNA (saRNA) enables sustained protein expression from a single administration. In this study, we developed an intramuscular saRNA-lipid nanoparticle (saNppa-LNP) therapy encoding natriuretic peptide type A (Nppa) for cardioprotection. A single injection induced sustained pro–atrial natriuretic peptide (pro-ANP) secretion for 4 weeks; pro-ANP was subsequently cleaved by the cardiac protease corin into active ANP, producing robust cardioprotection in mouse and swine myocardial infarction models. At equivalent doses, saNppa achieved greater efficacy than conventional mRNA. Single-nucleus transcriptomics identified natriuretic peptide receptor 1–positive (Npr1+) endothelial and epicardial cells as primary effectors, with saNppa-LNPs reshaping their paracrine profile to promote cardiomyocyte regeneration and suppress fibrosis. Longitudinal biosafety assessments revealed no systemic toxicity. Together, these results demonstrate that one-shot saNppa-LNP therapy offers durable cardioprotection, supporting the broader potential of saRNA-LNP–based approaches for cardiac therapy. Editor's summary: When a patient experiences a myocardial infarction, rapid intervention can prevent death and limit the progression of hypoxic damage, but treatment itself can worsen tissue injury due to oxidative damage in the setting of rapid reperfusion. Unfortunately, adult hearts cannot regenerate on their own, and previous attempts at inducing regeneration have been invasive, risky, or ineffective. To address this gap, Zhang et al. designed a self-amplifying RNA lipid nanoparticle to deliver the gene for atrial natriuretic peptide, a hormone that helps to maintain cardiovascular homeostasis (see the Perspective by Ervijn and Sanders). A single intramuscular injection of this treatment was safe and effective at promoting long-lasting recovery of the heart in numerous mouse and pig models of myocardial infarction, demonstrating its translational potential. —Yevgeniya Nusinovich INTRODUCTION: Myocardial infarction (MI) causes irreversible loss of cardiomyocytes and adverse remodeling, ultimately progressing to heart failure. Although gene- and RNA-based therapies offer promising strategies for cardiac repair, current approaches often rely on invasive myocardial delivery or are limited by short expression duration and low protein yields of conventional mRNA. Therefore, the development of a minimally invasive therapeutic platform that enables durable expression of cardioprotective factors remains a critical unmet need in cardiac therapy. RATIONALE: Atrial natriuretic peptide (ANP), encoded by natriuretic peptide type A (Nppa), is a developmentally regulated cardiac hormone with promising cardioprotective functions. We observed that Nppa expression was induced in both neonatal and adult mouse hearts after MI; however, the magnitude of induction was markedly greater in regenerative neonatal hearts. This disparity suggested that higher levels of Nppa expression may be associated with enhanced regenerative capacity and that insufficient Nppa induction may limit cardiac repair in adults. To address this, we developed a self-amplifying RNA (saRNA) therapy delivered via lipid nanoparticles (LNPs) to drive additional Nppa expression. Unlike mRNA, saRNA enables intracellular RNA replication, resulting in prolonged protein expression at substantially lower doses. We hypothesized that a single intramuscular (IM) injection of an saRNA-LNP encoding native Nppa (saNppa-LNP) could establish an in vivo "RNA factory," continuously producing circulating pro-ANP that is selectively activated into functional ANP in the heart by the cardiac protease corin, thereby providing durable cardioprotection without direct cardiac manipulation. RESULTS: A single IM injection of saNppa-LNPs in mice induced robust pro-ANP secretion lasting at least 4 weeks, outperforming mRNA at equivalent doses. In mouse models of acute MI and ischemia/reperfusion (I/R) injury, saNppa-LNP treatment markedly improved left ventricular ejection fraction, reduced infarct size, and attenuated fibrosis. These therapeutic benefits were consistently reproduced in aged, atherosclerotic, and diabetic MI models. In addition, large-animal studies in a swine I/R model further confirmed that a single IM injection effectively preserved cardiac function and limited maladaptive remodeling. Mechanistically, single-nucleus transcriptomics revealed that saNppa-LNP treatment reshaped the paracrine profile of natriuretic peptide receptor 1–positive (Npr1+) endothelial and epicardial cells, creating a proregenerative microenvironment that promoted cardiomyocyte cell-cycle reentry and suppressed the expansion of profibrotic periostin-positive (Postn+) fibroblasts. Longitudinal safety assessments revealed only transient local inflammation, with no evidence of adaptive immune activation or systemic toxicity. CONCLUSION: Our study demonstrates that a single IM administration of saNppa-LNPs provides robust and durable cardioprotection across multiple species and clinically relevant injury models. By leveraging the self-amplifying properties of saRNA and the heart-specific activation of pro-ANP, this minimally invasive, one-shot therapy may offer a safe, simple, and effective strategy for cardiac repair. Intramuscular injectable saNppa-LNP therapy for durable cardioprotection.: A single IM injection of saNppa-LNPs enables self-amplification and high-yield pro-ANP production for more than 28 days. Circulating pro-ANP is selectively cleaved by the cardiac protease corin into active ANP, activating NPR1/cGMP signaling in the heart. At equivalent doses, this minimally invasive, long-acting approach confers greater cardioprotection efficacy compared with conventional mRNA. GTP, guanosine triphosphate; cGMP, cyclic guanosine 3′,5′-monophosphate; UTR, untranslated region. [Figure created with BioRender.com] [ABSTRACT FROM AUTHOR]
Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Single intramuscular injection of self-amplifying RNA of Nppa to treat myocardial infarction.
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  Data: <searchLink fieldCode="AR" term="%22Zhang%2C+Kaiyue%22">Zhang, Kaiyue</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Tao%2C+Hongyan%22">Tao, Hongyan</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Zhu%2C+Dashuai%22">Zhu, Dashuai</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Yue%2C+Zhang%22">Yue, Zhang</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Hu%2C+Shiqi%22">Hu, Shiqi</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Wu%2C+Yiping%22">Wu, Yiping</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Yan%2C+Na%22">Yan, Na</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Hu%2C+Yilan%22">Hu, Yilan</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Liu%2C+Shuo%22">Liu, Shuo</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Liu%2C+Mengrui%22">Liu, Mengrui</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Vahl%2C+Torsten+Peter%22">Vahl, Torsten Peter</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ranard%2C+Lauren+Sharan%22">Ranard, Lauren Sharan</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Cheng%2C+Xiao%22">Cheng, Xiao</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Romanov%2C+Alexander%22">Romanov, Alexander</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Liu%2C+Jiaming%22">Liu, Jiaming</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Zhang%2C+Savannah+Weihang%22">Zhang, Savannah Weihang</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Li%2C+Yuan%22">Li, Yuan</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Lu%2C+Chao%22">Lu, Chao</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Shen%2C+Ming%22">Shen, Ming</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Lewis%2C+Andrew%22">Lewis, Andrew</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22Science%22">Science</searchLink>. 3/5/2026, Vol. 391 Issue 6789, p1-14. 14p.
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  Data: <searchLink fieldCode="DE" term="%22Intramuscular+injections%22">Intramuscular injections</searchLink><br /><searchLink fieldCode="DE" term="%22Myocardial+infarction%22">Myocardial infarction</searchLink><br /><searchLink fieldCode="DE" term="%22Atrial+natriuretic+peptides%22">Atrial natriuretic peptides</searchLink><br /><searchLink fieldCode="DE" term="%22Cardiac+regeneration%22">Cardiac regeneration</searchLink><br /><searchLink fieldCode="DE" term="%22Cardiotonic+agents%22">Cardiotonic agents</searchLink><br /><searchLink fieldCode="DE" term="%22Natriuretic+peptides%22">Natriuretic peptides</searchLink><br /><searchLink fieldCode="DE" term="%22Nucleic+acid+amplification+techniques%22">Nucleic acid amplification techniques</searchLink><br /><searchLink fieldCode="DE" term="%22Liposomes%22">Liposomes</searchLink>
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  Label: Abstract
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  Data: Self-amplifying RNA (saRNA) enables sustained protein expression from a single administration. In this study, we developed an intramuscular saRNA-lipid nanoparticle (saNppa-LNP) therapy encoding natriuretic peptide type A (Nppa) for cardioprotection. A single injection induced sustained pro–atrial natriuretic peptide (pro-ANP) secretion for 4 weeks; pro-ANP was subsequently cleaved by the cardiac protease corin into active ANP, producing robust cardioprotection in mouse and swine myocardial infarction models. At equivalent doses, saNppa achieved greater efficacy than conventional mRNA. Single-nucleus transcriptomics identified natriuretic peptide receptor 1–positive (Npr1+) endothelial and epicardial cells as primary effectors, with saNppa-LNPs reshaping their paracrine profile to promote cardiomyocyte regeneration and suppress fibrosis. Longitudinal biosafety assessments revealed no systemic toxicity. Together, these results demonstrate that one-shot saNppa-LNP therapy offers durable cardioprotection, supporting the broader potential of saRNA-LNP–based approaches for cardiac therapy. Editor's summary: When a patient experiences a myocardial infarction, rapid intervention can prevent death and limit the progression of hypoxic damage, but treatment itself can worsen tissue injury due to oxidative damage in the setting of rapid reperfusion. Unfortunately, adult hearts cannot regenerate on their own, and previous attempts at inducing regeneration have been invasive, risky, or ineffective. To address this gap, Zhang et al. designed a self-amplifying RNA lipid nanoparticle to deliver the gene for atrial natriuretic peptide, a hormone that helps to maintain cardiovascular homeostasis (see the Perspective by Ervijn and Sanders). A single intramuscular injection of this treatment was safe and effective at promoting long-lasting recovery of the heart in numerous mouse and pig models of myocardial infarction, demonstrating its translational potential. —Yevgeniya Nusinovich INTRODUCTION: Myocardial infarction (MI) causes irreversible loss of cardiomyocytes and adverse remodeling, ultimately progressing to heart failure. Although gene- and RNA-based therapies offer promising strategies for cardiac repair, current approaches often rely on invasive myocardial delivery or are limited by short expression duration and low protein yields of conventional mRNA. Therefore, the development of a minimally invasive therapeutic platform that enables durable expression of cardioprotective factors remains a critical unmet need in cardiac therapy. RATIONALE: Atrial natriuretic peptide (ANP), encoded by natriuretic peptide type A (Nppa), is a developmentally regulated cardiac hormone with promising cardioprotective functions. We observed that Nppa expression was induced in both neonatal and adult mouse hearts after MI; however, the magnitude of induction was markedly greater in regenerative neonatal hearts. This disparity suggested that higher levels of Nppa expression may be associated with enhanced regenerative capacity and that insufficient Nppa induction may limit cardiac repair in adults. To address this, we developed a self-amplifying RNA (saRNA) therapy delivered via lipid nanoparticles (LNPs) to drive additional Nppa expression. Unlike mRNA, saRNA enables intracellular RNA replication, resulting in prolonged protein expression at substantially lower doses. We hypothesized that a single intramuscular (IM) injection of an saRNA-LNP encoding native Nppa (saNppa-LNP) could establish an in vivo "RNA factory," continuously producing circulating pro-ANP that is selectively activated into functional ANP in the heart by the cardiac protease corin, thereby providing durable cardioprotection without direct cardiac manipulation. RESULTS: A single IM injection of saNppa-LNPs in mice induced robust pro-ANP secretion lasting at least 4 weeks, outperforming mRNA at equivalent doses. In mouse models of acute MI and ischemia/reperfusion (I/R) injury, saNppa-LNP treatment markedly improved left ventricular ejection fraction, reduced infarct size, and attenuated fibrosis. These therapeutic benefits were consistently reproduced in aged, atherosclerotic, and diabetic MI models. In addition, large-animal studies in a swine I/R model further confirmed that a single IM injection effectively preserved cardiac function and limited maladaptive remodeling. Mechanistically, single-nucleus transcriptomics revealed that saNppa-LNP treatment reshaped the paracrine profile of natriuretic peptide receptor 1–positive (Npr1+) endothelial and epicardial cells, creating a proregenerative microenvironment that promoted cardiomyocyte cell-cycle reentry and suppressed the expansion of profibrotic periostin-positive (Postn+) fibroblasts. Longitudinal safety assessments revealed only transient local inflammation, with no evidence of adaptive immune activation or systemic toxicity. CONCLUSION: Our study demonstrates that a single IM administration of saNppa-LNPs provides robust and durable cardioprotection across multiple species and clinically relevant injury models. By leveraging the self-amplifying properties of saRNA and the heart-specific activation of pro-ANP, this minimally invasive, one-shot therapy may offer a safe, simple, and effective strategy for cardiac repair. Intramuscular injectable saNppa-LNP therapy for durable cardioprotection.: A single IM injection of saNppa-LNPs enables self-amplification and high-yield pro-ANP production for more than 28 days. Circulating pro-ANP is selectively cleaved by the cardiac protease corin into active ANP, activating NPR1/cGMP signaling in the heart. At equivalent doses, this minimally invasive, long-acting approach confers greater cardioprotection efficacy compared with conventional mRNA. GTP, guanosine triphosphate; cGMP, cyclic guanosine 3′,5′-monophosphate; UTR, untranslated region. [Figure created with BioRender.com] [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
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  Data: <i>Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1126/science.adu9394
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      – SubjectFull: Atrial natriuretic peptides
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