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The objective of the study was to assess the therapeutic efficacy of targeting remote zone cardiomyocytes with cardiosphere‐derived cell (CDC) extracellular vesicles (EVs) delivered via intramyocardial and intravenous routes following acute myocardial infarction (MI). Cardiomyocyte (CM) cell death plays a significant role in left ventricular (LV) remodeling and cardiac dysfunction following MI. While EVs secreted by CDCs have shown efficacy in promoting cardiac repair in preclinical models of MI, their translational potential is limited by their biodistribution and requirement for intramyocardial delivery. We hypothesized that engineering the surface of EVs to target cardiomyocytes would enhance their therapeutic efficacy following systemic delivery in a model of acute MI. CDC‐derived EVs were engineered to express a CM‐specific binding peptide (CMP) on their surface and characterized for size, morphology, and protein expression. Mice with acute MI underwent both intramyocardial and intravenous delivery of EVs, CMP‐EVs and placebo in a double‐blind study. LVEF was assessed by echo at 2‐ and 28‐days post‐MI and tissue samples processed for assessment of EV biodistribution and histological endpoints. CMP‐EVs demonstrated superior cardiac targeting and retention when compared with unmodified EVs 24 h post‐MI. Mice treated with IV delivered CMP‐EVs demonstrated a significant improvement in LVEF and a significant reduction in remote zone cardiomyocyte apoptosis when compared with IV delivered non‐targeted EVs at 28‐day post‐MI. Systemic administration of CMP‐EVs improved cardiac function and reduced remote zone cardiomyocyte apoptosis compared with IV‐administered unmodified EVs, demonstrating a strategy to optimize therapeutic EV delivery post‐MI. [ABSTRACT FROM AUTHOR]