Abstract
Effective drug delivery relies on the selection of suitable carriers, which is crucial for protein-based therapeutics such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). One of the key advantages of TRAIL is its ability to selectively induce apoptosis in cancer cells excluding healthy tissues by binding to death receptors DR4 and DR5, which are highly expressed in various cancer cells. Despite this promise, the clinical application of TRAIL has been limited by its short half-life, limited stability, and inefficient delivery to tumor sites. To overcome currently available clinical and engineering approaches, a series of sophisticated strategies is required: (a) the design of biomaterial-mediated carriers for enhanced targeting efficacy, particularly via optimizing selected materials, composition, formulation, and surface modulation. Moreover, (b) development of genetically modified cellular products for augmented TRAIL secretion toward tumor microenvironments and (c) cell surface engineering techniques for TRAIL immobilization onto infusible cell populations are also discussed in the present review. Among these approaches, living cell-based carriers offer the distinct advantage of systemically administered TRAIL-functionalized cells capturing circulating tumor cells in the bloodstream, thereby preventing secondary tumor formation. This review provides insight into the development of novel TRAIL delivery platforms, discusses considerations for clinical translation, and suggests future directions and complementary strategies to advance the field of TRAIL-based cancer therapeutics.