Decoy Oligonucleotides in Cancer Therapy: Mechanisms, Challenges, and Clinical Potential
Cancer researchers are turning a deceptively simple piece of DNA into a molecular “decoy” that could disrupt the genetic commands driving tumors.
Decoy oligonucleotides are short synthetic nucleic‑acid sequences designed to imitate DNA motifs recognized by oncopromoting transcription factors such as STAT3, NF‑κB, and Ets‑1. By sequestering these factors in the nucleus, the decoys prevent binding to endogenous promoters/enhancers, thereby interrupting the transcription of genes involved in proliferation, survival, invasion, angiogenesis, inflammation, and metabolic reprogramming. The review summarizes the molecular logic of decoy action, the experimental evidence in cell‑culture and animal models, the first‑in‑human experience in head and neck tumors, and the delivery challenges that remain before clinical application. Delivery strategies include chemical modifications, circular ‘dumbbell’ architectures, liposomes, polymeric nanoparticles, and biomaterial carriers. The article discusses the potential for combination with conventional therapies and immune modulators, the risk of innate immune activation, and the need for rigorous pharmacokinetic and safety studies.
By acting upstream of gene transcription, decoy oligonucleotides have the potential to shut down multiple oncogenic pathways simultaneously, offering a new strategy to overcome resistance that arises when single‑target drugs are employed.
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