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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.