Tumor targeted radionuclide-nanomedicine for clinical translation: From carrier innovation to precision therapy.

Targeted radionuclide therapy (RNT) precisely delivers radiation to tumors, yet solid tumors remain challenging due to heterogeneous target expression, poor intratumoral delivery, and off-target exposure to normal organs. As an emerging paradigm in precision oncology, tumor targeted radionuclide-nanomedicines provide a structural and functional platform to overcome the vector-dependent limitations of conventional radiopharmaceuticals. They improve the in vivo stability of radiolabeled small-molecule and peptide conjugates, normally vulnerable to enzymatic degradation and rapid renal clearance by providing protective encapsulation, albumin engagement, or polymer-based shielding. In parallel, they optimize the biodistribution of antibody-based vectors by modulating size, charge, and Fc interactions, thereby reducing off-target renal and hepatic uptake while preserving high tumor specificity. This review summarizes recent advances in engineered nanoplatforms, including core-shell structures for enhanced isotope retention, dual-targeting and albumin hitchhiking for improved tumor accumulation, and stimuli-responsive chemistries that synchronize isotope release with tumor microenvironmental regulation effects. Preclinical and clinical advances span image-addressable convection-enhanced delivery of nanoliposomes that enable see-then-treat radiotheranostic workflows, compact albumin-binding self-assembly systems that extend circulation and increase tumor exposure, and systemic albumin-engaged radioligands that establish principles for nanopharmacokinetic and pharmacodynamic design. This review also critically evaluates the clinical prospects and remaining challenges, including variability in the enhanced permeability and retention effect, protein corona formation and complement activation, α-emitter containment, adherence to current good manufacturing practice standards, and the growing need for individualized dosimetry. By integrating nanoplatform design with mechanistic insights, this review provides a comprehensive, timely overview of next-generation RNT and offers practical guidance for advancing its clinical translation.