Sulaiman, Elias; (2025) The fatty acid transporter, CD36, mediates cellular uptake, in vivo biodistribution and cardioprotection by HEK293-derived small extracellular vesicles. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Small extracellular vesicles (sEV) are nanosized particles comprised of a lipid bilayer, containing a rich biological cargo. sEV facilitate intracellular communication. In recent years, sEV have garnered significant attention for their therapeutic potential in myocardial infarction, as they can reduce the infarct size and improve cardiac function in preclinical animal models. Despite rigorous research, critical gaps remain in understanding the biodistribution, cellular interaction and mechanisms of protection by sEV. This project aimed to address some of these gaps by investigating the cellular kinetics of sEV in the cardiac tissue, their in vivo biodistribution, and potential cardioprotection, with the aim of discovering novel pathways that mediate these effects. To achieve this, human embryonic kidney 293 (HEK293) cells were transiently transfected with a plasmid to enable production of luminescent sEV, which were then isolated using tangential flow filtration and further biochemically and physically characterised. It was shown that several different human endothelial cell types rapidly internalise HEK293-derived sEV, in a dose-dependent manner. In contrast, uptake of sEV into rat cardiomyocytes was significantly slower and followed a time-dependent response. Importantly, the CD36 fatty acid transporter was identified as an important mediator of sEV uptake, as its inhibition led to a reduction in sEV internalisation. Investigation of their in vivo distribution after intravenous injection in mice revealed that HEK293-sEV primarily localise to the lungs and liver. Importantly, intravenous sEV administration reduced the infarct size in a reperfused mouse model of myocardial infarction. In support of CD36 being important for sEV uptake, inhibition of CD36 reduced organ localisation and abolished the cardioprotective effects of sEV in vivo. Overall, this project provides new insights into sEV kinetics and reveals that CD36 contributes to sEV distribution, cellular uptake and cardioprotective function.

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