A Modular Supramolecular Peptide Platform Reveals Atomic-Number-Dependent Mechanisms Driving Radioenhancement

Optimizing radioenhancer design for cancer therapy has been limited by inconsistent metal comparisons and unclear nanoscale mechanisms. High-Z nanoparticles are expected to enhance radiation effects through increased photoelectric absorption and secondary electron production, with the common assumption that radioenhancement efficacy increases uniformly with atomic number. However, this linear relationship may be oversimplified. Here, we introduce a versatile, supramolecular peptide platform enabling direct and standardized comparison of gadolinium (Gd), bismuth (Bi), and hafnium (Hf) as radioenhancers within a single, biologically targeted framework. This system is based on autoassembled peptide heterodimers (E3-K3) incorporating a flexible chelator (DOTAGA) and variable heavy-chain antibody (VHH) domains, ensuring uniform cellular uptake and precise tumor targeting. Systematic in vitro and in vivo analyses across HER2+ breast cancer and disseminated multiple myeloma models demonstrate that radioenhancement efficacy correlates with atomic number but not in a simple linear fashion, with physicochemical properties of each metal determining biological outcomes such as DNA damage induction, reactive oxygen species generation, and clonogenic survival reduction. Specifically, Gd- and Bi-loaded formulations significantly enhanced tumor control under external beam radiotherapy, with Bi exhibiting superior efficacy, while Gd-based constructs facilitated MRI-guided radioligand therapy. Our study elucidates fundamental physical mechanisms governing metal-dependent radioenhancement at the nanoscale but also establishes a broadly applicable theranostic approach with significant translational implications for personalized radiation oncology.