Despite advancements in the development of targeted approaches for the treatment of myocardial infarction (MI), there is a continuing need for improvements in treatment approaches due to the high mortality and prevalence of MI. The identification of specific therapeutic targets and the development of efficient delivery systems are essential. In this study, a nanoparticle delivery system targeting necrotic cardiomyocytes was engineered. This system effectively downregulated long noncoding RNA (lncRNA) AK156373 and reduced oxidative stress and inflammation during MI progression. Mechanistically, silencing lncRNA AK156373 enhanced the viability and mitochondrial function of hypoxic cardiomyocytes and lowered intracellular inflammatory cytokine levels and reactive oxygen species (ROS) production.