Abstract
Radiopharmaceuticals deliver diagnostic or therapeutic radionuclides to disease sites with molecular precision. Over the past five years, clinical adoption has accelerated, led by U.S. Food and Drug Administration approvals of (177)Lu-DOTA-TATE and (177)Lu-PSMA-617 and their complementary Positron Emission Tomography agents ((68)Ga-DOTA-TATE, (68)Ga-PSMA-11), which have established radiotheranostics as a pillar of oncology care. The new generation of agents couples optimized radionuclides (β(-), α, and Auger emitters) to antibodies, peptides, and small-molecule vectors that improve tumor uptake, residence time, and clearance profiles, thereby enhancing efficacy and safety. Beyond neuroendocrine tumors and prostate cancer, radiotheranostic strategies are advancing for diverse malignancies by exploiting tumor-specific antigens, overexpressed receptors, and intracellular targets. Notably, α-emitters such as (225)Ac and (211)At-owing to high linear energy transfer and short path length-show potent cytotoxicity with limited off-target injury, while emerging β/Auger emitters like (161)Tb may surpass (177)Lu in microdosimetric effectiveness. Concurrent innovations in patient selection and response prediction leverage diagnostic radiopharmaceuticals for image-guided stratification, individualized dosimetry, and adaptive treatment planning, supporting the broader paradigm of precision medicine. Although oncology remains the primary focus, applications are expanding to neurodegeneration, cardiovascular disease, and inflammatory conditions. This review synthesizes technological and clinical progress from 2021-2025, spanning FDA-approved and late-stage investigational agents; mechanisms of radiopharmaceutical-induced cell death; dosimetry methodologies; trial landscapes for expanding indications; and translational challenges, including supply chains, chelation chemistry, and toxicity management. Accordingly, this review focuses on the latest radiopharmaceutical diagnostic and therapeutic technologies, integrating advances in radionuclide platforms, targeting vectors, dosimetry, and clinical trial data from 2021-2025 to guide future development and clinical implementation of precision radiotheranostics.