Self-assembled extracellular matrix-lipid nanoparticle composite for site-specific siRNA delivery to improve cardiac repair post-myocardial infarction

Cardiovascular disease remains a leading cause of mortality, highlighting the critical need for novel therapeutic strategies. RNA-based therapeutics, including siRNA and mRNA, offer promising approaches for cardiac diseases, yet their clinical application is limited by low heart specificity and suboptimal delivery methods. Lipid nanoparticles (LNPs) are widely used for RNA delivery but often accumulate in non-cardiac tissues, reducing their effectiveness. To address this, an extracellular matrix (ECM)-LNP composite is developed for targeted RNA delivery to the myocardium. The LNPs are conjugated to the ECM scaffold to enhance RNA retention. <i>In vivo</i> experiments demonstrate effective mRNA delivery and expression within the heart, with preferential targeting towards immune cells. Epidermal growth factor receptor (EGFR), a key regulator of cell proliferation and inflammation, is found to affect macrophage polarization in this study. The therapeutic potential of EGFR siRNA delivered via ECM-LNP composite is further explored in a mouse model of myocardial infarction (MI). Results indicate that ECM-siEGFR@LNP reduces cardiac fibrosis and promotes M2 macrophage polarization. This effect is associated with down-regulation of the EGFR-AKT signaling pathway. In conclusion, this study presents an injectable platform for heart-specific RNA delivery and sheds light on the role of EGFR signaling in the cardiac repair process.