Targeted engineered exosomes alleviate myocardial infarction injury by enhancing angiogenesis and improving mitochondrial function.

Myocardial infarction (MI) remains a leading cause of global mortality, where acute ischemic injury and chronic cardiomyocyte dysfunction are pathological mechanisms leading to heart failure (HF). Current therapies fail to effectively halt this progression. Although VegfA delivery shows potential for revascularization, its clinical translation is limited by inefficient delivery systems. Exosomes, as emerging nanocarriers, hold promise but suffer from poor targeting. Here, a dual mRNA-loaded exosome platment (ExoIC-LNV) for synergistic therapy is developed. The exosome is functionally designed with ischemic myocardium targeting peptide (IMTP) and Connexin 43 (Cx43) to accumulate at the ischemic region. Meanwhile, ExoIC-LNV contains VegfA mRNA and Ndufs1 mRNA, based on the binding properties of L7Ae. The results demonstrate that ExoIC-LNV achieve significantly higher enrichment in ischemic tissue compared to single targeted modified exosomes. The Ndufs1-loaded exosomes improve mitochondrial function in hypoxic cardiomyocytes, and the VefgA-loaded exosomes promote angiogenesis in ischemic tissue. ExoIC-LNV loaded with dual mRNAs exhibit superior mitochondrial improvement while promoting angiogenesis, resulting in better cardiac function improvement through dual-pathway modulation after MI. Through multiple tail vein injections, the benefical proteins accumulate in the ischemic area, providing better prospects for clinical translation. This study proposes a targeted exosome-based strategy for combating pathological remodeling in MI and represents a possible approach for HF prevention.