Targeting Ischemic Myocardium: Nanoparticles Loaded with Long Noncoding RNA AK156373 siRNA Alleviate Myocardial Infarction

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. <i>In vivo</i>, cardiac-specific lncRNA AK15673 knockout mice were generated (AK156373^{flox/flox, Myh6-Cre} mice), and lncRNA AK156373 knockout obviously reduced the infarct size, collagen fiber deposition, and ischemia severity in MI mice, leading to improved cardiac function. Additionally, lncRNA AK156373 modulated miR-204-5p to regulate C-X-C motif chemokine receptor 2 (CXCR2) protein expression via the competing endogenous RNA (ceRNA) mechanism, exacerbating myocardial damage and accelerating MI progression. Subsequently, nanoparticles loaded with lncRNA AK156373 siRNA were synthesized. The nanoparticles significantly inhibited MI progression by modulating the miR-204-5p/CXCR2 axis to reduce oxidative stress and inflammation. Overall, these findings establish a key regulatory role for lncRNA AK156373 in MI progression and present a direct preclinical approach for MI therapy.