Medical isotope-labeled nucleic acids: A decade of progress toward theranostics (2015-2025)

Medical isotope-labeled nucleic acids represent an emerging theranostic platform at the intersection of radiochemistry and oligonucleotide therapeutics. This review surveys studies published between 2015 and 2025, examining radiochemistry fundamentals essential for clinical translation: isotope selection matching biological half-lives to radioactive decay, labeling strategies employing prosthetic groups as well as chelators, and quality control metrics that provide benchmarks for preliminary study-to-study comparison. Two biological targeting modalities are examined: aptamers that bind cell-surface receptors and pre-targeting approaches with peptide nucleic acid-labeled antibodies that are inaccessible to other imaging modalities. Pre-targeting strategies, which deploy sequential administration of nonradioactive and radiolabeled probes achieve 70-fold enhancement in tumor uptake. The field has crossed critical translational thresholds: first-in-human safety validation, high tumor uptake in preclinical animal models, and successful therapeutic isotope deployment. Persistent challenges include rapid clearance, renal retention of radioactivity, and suboptimal tumor-to-background ratios requiring systematic optimization. Radiolabeled oligonucleotides are a compelling platform for precision medicine.