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

  • Science. 2026 Mar 5;391(6789):edau9394. doi: 10.1126/science.adu9394.
Kaiyue Zhang  1 ,  Hongyan Tao  2 ,  Dashuai Zhu  1 ,  Zhang Yue  1 ,  Shiqi Hu  1 ,  Yiping Wu  1 ,  Na Yan  1 ,  Yilan Hu  1 ,  Shuo Liu  1 ,  Mengrui Liu  1 ,  Torsten Peter Vahl  3  4 ,  Lauren Sharan Ranard  3  4 ,  Xiao Cheng  1 ,  Alexander Romanov  5 ,  Jiaming Liu  1 ,  Savannah Weihang Zhang  1 ,  Yuan Li  1 ,  Chao Lu  1 ,  Ming Shen  1 ,  Andrew Lewis  2 ,  Ke Huang  1  6 ,  Ke Cheng  1  3  7
Affiliations
  • 1. Department of Biomedical Engineering, Columbia University, New York, NY, USA.
  • 2. University of Oxford Centre for Clinical Magnetic Resonance Research, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
  • 3. Seymour, Paul and Gloria Milstein Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • 4. Structural Heart and Valve Center, Columbia University Irving Medical Center, New York, NY, USA.
  • 5. Institute of Comparative Medicine at Columbia University, New York, NY, USA.
  • 6. Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University, Kingsville, TX, USA.
  • 7. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
PMID: 41785353 DOI: 10.1126/science.adu9394
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.

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