Curcumin-loaded extracellular vesicles endowed with heart targeting properties facilitate treatment of myocardial infarction

Abstract Background Myocardial infarction (MI) is a public health problem and a leading cause of death worldwide. Due to insufficient current treatments, it is essential to develop effective alternatives for MI treatment. Curcumin is known to exhibit a variety of protective effects on the cardiovascular system such as MI, hypertension, and diabetic cardiomyopathy. However, due to its low solubility/stability and quick systemic elimination, curcumin has limited bioavailability. Extracellular vesicles (EVs) have lately emerged as a promising drug delivery vehicles by overcoming drug delivery hurdles. However, strategies are needed for delivery of EVs into the heart avoiding accumulation of other organs. Purpose The aim of this study is to investigate whether curcumin-loaded EVs functionalized with cardiac targeting peptide (CTP) may function as efficient heart-targeted delivery vehicles of curcumin, and further identify the molecular mechanisms underlying curcumin-mediated therapeutic effects in the MI. Methods EVs functionalized to express CTP (CTP-EVs) were isolated from culture medium of HEK293 cells transfected with mCherry-CD81–10 plasmid and CTP-LAMP2 plasmid by differential centrifugation, and then loaded with curcumin by coincubation, named CTP-EVs-Cur. The effect of CTP-EVs-Cur were evaluated H9C2 cardiomyocytes and mouse MI model. For the in vivo experiments, CTP-EVs-Cur (approximately 8–10 × 109 particles) were administered by intravenous injection into the tail vein and mice were subjected to the left anterior descending (LAD) artery ligation with a 6–0 silk suture. Results CTP-EVs were safely and successfully delivered curcumin to H9C2 cardiomyocytes and mouse hearts (4-fold; P<0.05), and CTP-EVs-Cur have a protective effect against MI in vitro and in vivo models. After validating potential utility of CTP-EVs-Cur in MI treatment, we investigated the mechanism of curcumin-mediated recovery effects after MI. In H2O2 treated-cardiomyocytes, curcumin significantly reduced apoptosis by regulating the PTEN/AKT pathway following upregulation of miR-144-3p expression. Furthermore, mice injected with CTP-EVs-Cur reduced infarct size and apoptosis with the regulation of miR-144-3p/PTEN/Akt pathway. Conclusion These findings suggest highly stable/effective ability of CTP-EVs for heart-targeted delivery and the novel mechanism of curcumin-mediated cardioprotective effects after MI, therefore, CTP-EVs-Cur are potentially powerful therapeutic strategy for MI treatment. Funding Acknowledgement Type of funding source: None