TRAIL delivery by MSC-derived extracellular vesicles is an effective anticancer therapy

Area of Science:

• Biotechnology
• Cell Biology
• Cancer Research

Background:

• Extracellular vesicles (EVs) are nanoparticles mediating intercellular communication and hold promise for drug delivery.
• TNF-related apoptosis-inducing ligand (TRAIL) induces cancer cell apoptosis but faces clinical challenges like low bioavailability and resistance.
• Mesenchymal stromal cells (MSCs) are a potential source for therapeutic EV production.

Purpose of the Study:

• To investigate the expression of TRAIL in MSC-derived EVs.
• To evaluate the anticancer efficacy of TRAIL-expressing EVs (MSCT-EVs).
• To explore strategies for enhancing MSCT-EVs' therapeutic potential.

Main Methods:

• EVs were isolated from MSCs and TRAIL-expressing MSCs (MSCTs) using ultracentrifugation.
• EV characterization included size analysis (50-70 nm) and surface marker analysis (CD63, CD9, CD81, surface TRAIL).
• Cytotoxicity assays were performed on 11 cancer cell lines and primary bronchial epithelial cells, with mechanistic studies involving caspase inhibition and TRAIL neutralization.

Main Results:

• MSCT-EVs successfully expressed surface TRAIL, confirmed by marker analysis.
• MSCT-EVs demonstrated dose-dependent apoptosis induction in 11 cancer cell lines without harming normal cells.
• TRAIL-positive EV cytotoxicity was blocked by caspase inhibition or TRAIL neutralization, confirming the mechanism.
• MSCT-EVs effectively induced apoptosis in TRAIL-resistant cancer cells, with enhanced efficacy upon CDK9 inhibitor treatment.

Conclusions:

• TRAIL delivery via MSC-derived EVs represents a viable and effective anticancer therapeutic strategy.
• EV-mediated TRAIL delivery overcomes limitations associated with recombinant TRAIL, including cancer cell resistance.
• Combining MSCT-EVs with agents like CDK9 inhibitors may further potentiate their anticancer activity.