LNPs-mediated VEGF-C mRNA delivery promotes heart repair and attenuates inflammation by stimulating lymphangiogenesis post-myocardial infarction.

Abstract

Myocardial infarction (MI) initiates a strong inflammatory response, leading to adverse ventricular remodeling. The reconstruction of functional lymphatic networks is indispensable for relieving myocardial edema and regulating post-infarction inflammation. However, conventional protein-based therapies and viral delivery systems aimed at promoting lymphangiogenesis in the heart have shown limited therapeutic efficacy due to their inherent limitations. In this study, a lipid nanoparticle (LNP) platform encapsulating VEGF-C mRNA was developed as a novel approach to regulate gene expression and stimulate sustained lymphatic neogenesis after MI. Intramyocardial delivery of VEGF-C mRNA-loaded LNPs significantly promoted lymphangiogenesis, reduced the infiltration of inflammatory cells, and inhibited pro-inflammatory and fibrosis-associated signaling pathways. This ultimately resulted in a substantial reduction in the fibrotic area and improved functional recovery. Our findings demonstrated that VEGF-C mRNA@LNPs repair myocardial ischemic injury by facilitating immune modulation through lymphatic neogenesis, offering a promising new therapeutic strategy with strong translational potential for treating myocardial infarction.