Abstract Body (Do not enter title and authors here): Background: Cardiomyocyte (CM) cell death is a sentinel event in the development of cardiomyopathy. It contributes to additional myocyte dysregulation, generating a positive-feedback loop which potentiates the evolution of heart disease. Accordingly, CMs represent an important therapeutic target in modulating the pathogenesis of cardiac disease. While extracellular vesicles derived from cardiosphere-derived cells (CDC-EVs) have emerged as therapeutic vectors for cardiovascular disease, their potential is limited by their biodistribution and necessity for direct intramyocardial injection. We hypothesized that CDC-derived EVs engineered to express a CM-specific binding peptide (CMP-EVs) with improved cardiac targeting would result in enhanced therapeutic efficacy when administered intravenously post-myocardial infarction (MI).

Methods: Mice with acute MI underwent both intramyocardial and intravenous (IV) delivery of unmodified CDC-EVs, CMP-EVs and vehicle control in a double-blind study. Left ventricular ejection fraction (LVEF) was assessed by echo at 2- and 28-days post-MI and tissue samples processed for assessment of EV biodistribution and histological endpoints.

Results: Mice treated with IV delivered CMP-EVs demonstrated a significant improvement in LVEF (57% ± 2% vs. 47% ± 3%) and a significant reduction in remote zone cardiomyocyte apoptosis (0.6 ± 0.2% vs. 1.9 ± 0.4%) when compared with IV delivered non-targeted EVs at 28-days post-MI (n=6-8 mice per group, mean± SEM, p<0.05, one-way ANOVA followed by Tukey’s post-hoc test).

Conclusions: Systemic administration of CMP-EVs enhances their ability to augment systolic function following acute MI when delivered via systemic route, demonstrating a strategy to optimize therapeutic EV delivery post-MI. This approach also facilitates repeated dosing which may be advantageous as a treatment strategy for several cardiovascular diseases.