TRAIL in the Treatment of Cancer: From Soluble Cytokine to Nanosystems

Simple Summary TRAIL is a death ligand cytokine, predominantly used by effector immune cells to kill malignantly transformed cells. Since its discovery, TRAIL has attracted a lot of attention as a promising anticancer drug due to its selective action against cancer cells, promising a safe, low-toxicity treatment. Despite its promising characteristics, clinical trials have not delivered on this promise, due to issues with the poor in vivo biological activity of recombinant TRAIL formulations. Nanoparticles have the potential to overcome these limitations, and an increasing number of studies have reported very promising preclinical results. Here, we summarize the potential of TRAIL for cancer therapy, and provide a critical assessment of the challenges and the potential of various formulations of nanovehicles designed to date for TRAIL-based cancer therapy. The death ligand tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF cytokine superfamily, has long been recognized for its potential as a cancer therapeutic due to its low toxicity against normal cells. However, its translation into a therapeutic molecule has not been successful to date, due to its short in vivo half-life associated with insufficient tumor accumulation and resistance of tumor cells to TRAIL-induced killing. Nanotechnology has the capacity to offer solutions to these limitations. This review provides a perspective and a critical assessment of the most promising approaches to realize TRAIL's potential as an anticancer therapeutic, including the development of fusion constructs, encapsulation, nanoparticle functionalization and tumor-targeting, and discusses the current challenges and future perspectives.