Prospects of covalent radionuclide drug conjugates: Research and development progress

Targeted radionuclide therapy (TRT) is a key modality for the precision diagnosis and treatment of advanced malignancies. Radionuclide drug conjugates (RDCs), the main delivery vehicles of TRT, have achieved important clinical successes, but insufficient tumor retention remains the critical bottleneck limiting the full efficacy of long-half-life therapeutic radionuclides. Covalent RDCs equip ligand scaffolds with latent electrophilic warheads that, driven by the proximity effect, form reversible or irreversible covalent bonds with nucleophilic residues on target proteins, aiming to prolong tumor retention while preserving favorable systemic pharmacokinetics—an important design objective rather than an intrinsic, guaranteed property. This review summarizes the mechanism of action, structural composition and research progress of covalent RDCs, covering representative agents targeting FAP, PSMA, NTSR1, KRAS G12C and HER2. It provides a dedicated comparison of six covalent warheads—aryl fluorosulfate, maleimide, acrylamide, epoxysuccinyl, carbamate and ketobenzothiazole—in terms of reaction features, targeted residues, advantages and limitations, and distills molecular design principles. It further consolidates emerging considerations on safety, dosimetry, manufacturing and regulatory issues associated with covalent retention, and outlines how artificial intelligence-driven drug design may assist covalent ligand discovery and warhead reactivity optimization, separating demonstrated applications from future prospects. Finally, key challenges are critically discussed, including the balance between tumor retention and normal-tissue exposure, and the gap between encouraging preclinical findings and mature clinical validation.