Engineering Small Extracellular Vesicle-Derived Vehicles Carrying Optimized microRNA for Cardiac Repair after Myocardial Infarction

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Bheri, Sruti
Davis, Michael E.
Platt, Manu O.
Serpooshan, Vahid
Champion, Julie A.
Cho, Hee Cheol
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Myocardial infarction (MI) is one of the leading causes of morbidity and mortality worldwide. One promising therapy involves delivering small extracellular vesicles (sEVs). These sEVs are 30-150 nm vesicles containing protein and/or nuclear cargo. Despite their reparative potential, sEV therapies have several issues due to their cellular origin, including variable sEV yield and uncontrolled and low-density cargo encapsulation. Synthetic sEV-mimics have been developed which allow optimized cargo loading but these have high toxicity, compromised membranes and poor uptake. Therefore, there is a need for cell-free vehicles with sEV-like membrane and uptake, which allow delivery of customized cargo. To address these needs, the aim of this study was (1) to develop an sEV-like vehicle (ELV) with select microRNA (miR) cargo for cardiac repair and (2) to understand the role of the sEV membrane on vesicle uptake and ELV functionality. We hypothesized that ELVs comprised of an sEV membrane and loaded with miR cargo will improve cardiac tissue repair after MI compared to sEVs alone and that membrane composition will affect ELV functionality. The ELVs were loaded with miR-126, an endothelial marker, and when administered to cardiac endothelial cells, improved angiogenesis compared to sEV treatment. We then injected miR-126+ELVs into a rat model of ischemia-reperfusion wherein the ELVs reduced infarct size, fibrosis and hypertrophy and increased angiogenic parameters. We then assessed the relationship between sEV membrane composition and uptake mechanism finding that sEV origin affects both composition and uptake. We tested this by engineering miR-126+ELVs from two cell types and found differences in their angiogenic and proliferative capacity. Taken together, this study demonstrates the value of engineering vehicles with sEV membranes and their potential to deliver selective cargo for cardiac repair after MI.
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