Novel modifications of small extracellular vesicles to enhance cardiac-specific delivery of siPKA RNA and edaravone against ischemia-reperfusion cardiac injury

Relative tight endothelium in the heart may be a barrier for drugs in the large molecule and nanoparticle formats to act on cardiomyocytes. We hypothesize that enhanced binding of large molecules or nanoparticles to the cardiac capillary endothelial cells can increase the transendothelial transport of these drugs to exert their effects on the cardiomyocytes beneath the endothelium. CD36 is densely localized on the membrane of myocardial endothelial cells and thus we engineered small extracellular vesicles (sEVs) to be coated with an analog of CD36 ligand fatty acids, KOdiA-PC. Further to trap more therapeutic sEVs in the myocardium, we conjugated the sEVs with ischemic myocardium- targeting peptide (IMT). These dual-modifications of sEVs resulted in markedly enhanced fluorescent retention in the MIRI heart, indicating the potential of this system as a promising drug delivery platform for ischemic myocardium. Thus we loaded the dually-modified sEVs with edaravone (EDV) and siPKA RNA to dampen the ROS and inhibit overactivated PKA in myocardium subjected to ischemia/reperfusion injury, making a multistage-targeting and multifunctional sEVs delivery system (KI-sEVs/siPKA/EDV). The results showed that KOdiA-PC modification significantly enhanced sEVs transendothelial transport efficiency, and dual-targeting modification dramatically increased the accumulation of sEVs in the heart. Intravenous injection of KI-sEVs/siPKA/EDV significantly decreased myocardial infarction size, improved cardiac function and reduced cardiac fibrosis in animals subjected to MIRI or MI. KI-sEVs/siPKA/EDV also showed good biocompatibility and low toxicity. Our study provides an innovative cardiac-targeting delivery strategy and offers a promising method for MIRI and Persistent coronary occlusion MI treatment.

Abstract from PubMed Central (PMID 42964572, PMC13720831). This entry was added automatically by our daily literature monitor because it matches the topics we follow; read the full paper at the original source.