Engineered exosomes with ischemic myocardium-targeting peptide for targeted therapy in myocardial infarction

Abstract

Background-Exosomes are membranous vesicles generated by almost all cells. Recent studies demonstrated that mesenchymal stem cell-derived exosomes possessed many effects, including antiapoptosis, anti-inflammatory effects, stimulation of angiogenesis, anticardiac remodeling, and recovery of cardiac function on cardiovascular diseases. However, targeting of exosomes to recipient cells precisely in vivo still remains a problem. Ligand fragments or homing peptides discovered by phage display and in vivo biopanning methods fused to the enriched molecules on the external part of exosomes have been exploited to improve the ability of exosomes to target specific tissues or organs carrying cognate receptors. Herein, we briefly elucidated how to improve targeting ability of exosomes to ischemic myocardium. Methods and Results-We used technology of molecular cloning and lentivirus packaging to engineer exosomal enriched membrane protein (Lamp2b) fused with ischemic myocardium-targeting peptide CSTSMLKAC (IMTP). In vitro results showed that IMTP-exosomes could be internalized by hypoxia-injured H9C2 cells more efficiently than blank-exosomes. Compared with blankexosomes, IMTP-exosomes were observed to be increasingly accumulated in ischemic heart area (P<0.05). Meanwhile, attenuated inflammation and apoptosis, reduced fibrosis, enhanced vasculogenesis, and cardiac function were detected by mesenchymal stem cell-derived IMTP-exosome treatment in ischemic heart area. Conclusions-Our research concludes that exosomes engineered by IMTP can specially target ischemic myocardium, and mesenchymal stem cell-derived IMTP-exosomes exert enhanced therapeutic effects on acute myocardial infarction.