TRAIL-functionalized nanoparticles in cancer therapy: Molecular mechanisms and translational opportunities.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent anticancer agent capable of selectively triggering apoptosis in malignant cells while sparing normal tissues. Clinical translation of TRAIL is limited by rapid systemic clearance, poor pharmacokinetics, and intrinsic or acquired tumor resistance. Nanotechnology offers innovative solutions by stabilizing TRAIL, enhancing bioavailability, and enabling targeted delivery. Lipid-based, polymeric, and metallic nanoparticles have been engineered to improve TRAIL activity and achieve tumor-specific accumulation. TRAIL-functionalized nanocarriers also facilitate combinatorial strategies, including co-delivery with chemotherapeutics, sensitizers, or immunomodulators, to overcome resistance and potentiate apoptotic signaling. Preclinical studies in triple-negative breast cancer, glioblastoma, and colorectal carcinoma models demonstrate enhanced therapeutic efficacy, reduced systemic toxicity, and significant translational potential. This review critically examines the molecular mechanisms of TRAIL-mediated apoptosis, design principles of TRAIL-conjugated nanoparticles, and their integration into synergistic therapeutic regimens. Current limitations and future directions are discussed, emphasizing strategies to advance TRAIL nanomedicines toward clinical application. Collectively, TRAIL-functionalized nanoparticles represent a promising approach to precision oncology, bridging molecular therapeutics and nanotechnology for personalized cancer treatment.