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bioRxiv · 10.1101/2022.01.31.478512

Surface engineering enhances the therapeutic potential of extracellular vesicles following acute myocardial infarction

Mentkowski, K. I.·Tarvirdizadeh, T.·Manzanero, C. A.·Eagler, L. A.·Lang, J. K.
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Abstract

Structured AbstractO_ST_ABSObjectivesC_ST_ABSThe objective of the study was to assess the therapeutic efficacy of targeting remote zone cardiomyocytes with cardiosphere-derived cell (CDC) extracellular vesicles (EVs) in acute myocardial infarction. BackgroundCardiomyocyte (CM) cell death plays a significant role in left ventricular (LV) remodeling and cardiac dysfunction following myocardial infarction (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. We hypothesized that targeting therapeutic EVs to CMs would result in further reduction of cardiomyocyte (CM) cell death in vivo and improvement in cardiac function post-MI. MethodsCDC-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 delivery of human CDC EVs, CMP-EVs and placebo in a double-blind study. LVEF was assessed by echo at 1- and 28-days post-MI and tissue samples processed for assessment of EV biodistribution and histological endpoints. ResultsCMP-EVs demonstrated superior cardiac targeting and retention when compared with control EVs 24 hours post MI. While intramyocardial administered CDC-EVs improved LVEF compared with placebo at 4 weeks, mice treated with CMP-EVs demonstrated a significant improvement in LVEF compared with non-targeted EVs. Likely accounting for their augmented therapeutic efficacy, CMP-EVs demonstrated enhanced reduction of remote zone cardiomyocyte apoptosis. ConclusionsTargeting CMP-EVs to CMs post-MI improved cardiac function compared with unmodified EVs demonstrating a strategy to further optimize therapeutic EV delivery to increase efficacy and decease off-target effects. Condensed AbstractExtracellular vesicles (EVs) offer several potential advantages over small molecule therapeutics for cardiovascular disease (CVD). However, their potential is limited by their biodistribution and lack of specificity. We engineered cardiosphere-derived cells (CDCs) to express Lamp2b fused to a cardiomyocyte specific peptide (CMP), generating EVs with increased cardiomyocyte uptake and cardiac retention. CMP-EVs enhanced cardiac function following acute MI and further reduced remote zone apoptosis when compared with unmodified CDC-EVs. This work highlights a role for targeting therapeutic EVs to cardiomyocytes following injury and serves as a proof-of-concept study for the utility of EV surface engineering in the treatment of CVD.

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Mentkowski, K. I., Tarvirdizadeh, T., Manzanero, C. A., Eagler, L. A., Lang, J. K.. 2022-02-02. Surface engineering enhances the therapeutic potential of extracellular vesicles following acute myocardial infarction. https://doi.org/10.1101/2022.01.31.478512

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