The Fatty Acid Transporter CD36 Mediates Uptake, Biodistribution, and Cardioprotection by Small Extracellular...

Extracellular vesicles (EVs) are nanoscale carriers of bioactive molecules that mediate intercellular communication. Small EVs (sEVs) have shown cardioprotective effects in models of myocardial infarction (MI), but their uptake and biodistribution remain incompletely understood. Here, we investigated NanoLuc-labelled HEK293-derived sEVs, assessing their uptake in cardiac cells, in vivo biodistribution, and effect on infarct size following cardiac ischaemia and reperfusion (IR) injury. We hypothesised that the scavenger receptor CD36, a lipid-binding receptor expressed in both cardiomyocytes and endothelial cells, may mediate sEV uptake. sEVs were purified by size-exclusion chromatography and tangential flow filtration. In vitro, cardiac endothelial cells internalised sEVs more efficiently than cardiomyocytes. In healthy mice, sEVs accumulated mainly in the lungs, liver, and spleen. However, when administered post-IR, sEVs significantly reduced infarct size (from 58% ± 8% to 36% ± 3%, p < 0.05, n = 5). Inhibition of CD36 with sulfosuccinimidyl oleate impaired sEV uptake and abolished cardioprotection. These findings suggest HEK293-sEVs may have therapeutic potential in MI and identify CD36 as a key mediator of their uptake and function.