TRAIL delivery by MSC-derived extracellular vesicles is an effective anticancer therapy.
Extracellular vesicles (EVs) are lipid membrane-enclosed nanoparticles released by cells. They mediate intercellular communication by transferring biological molecules and therefore have potential as innovative drug delivery vehicles. TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis of cancer cells. Unfortunately, the clinical application of recombinant rTRAIL has been hampered by its low bioavailability and resistance of cancer cells. EV-mediated TRAIL delivery may circumvent these problems. Mesenchymal stromal cells (MSCs) produce EVs and could be a good source for therapeutic EV production. We investigated if TRAIL could be expressed in MSC-derived EVs and examined their cancer cell-killing efficacy. EVs were isolated by ultracentrifugation and were membranous particles of 50-70 nm in diameter. Both MSC- and TRAIL-expressing MSC (MSCT)-derived EVs express CD63, CD9 and CD81, but only MSCT-EVs express surface TRAIL. MSCT-EVs induced apoptosis in 11 cancer cell lines in a dose-dependent manner but showed no cytotoxicity in primary human bronchial epithelial cells. Caspase activity inhibition or TRAIL neutralisation blocked the cytotoxicity of TRAIL-positive EVs. MSCT-EVs induced pronounced apoptosis in TRAIL-resistant cancer cells and this effect could be further enhanced using a CDK9 inhibitor. These data indicate that TRAIL delivery by MSC-derived EVs is an effective anticancer therapy.
Lungs for Living Research Centre, UCL Respiratory, Division of Medicine, University College London , London , UK.
ZhengQiang
Z
Yuan
Lungs for Living Research Centre, UCL Respiratory, Division of Medicine, University College London , London , UK.
Krishna K
KK
Kolluri
Lungs for Living Research Centre, UCL Respiratory, Division of Medicine, University College London , London , UK.
Kate H C
KH
Gowers
Lungs for Living Research Centre, UCL Respiratory, Division of Medicine, University College London , London , UK.
Sam M
SM
Janes
EV; MSC; TRAIL; cancer