Gadolinium-Doped Iron Oxide Nanoparticles Enhance Radiosensitivity in Melanoma Models Associated with Metabolic Dysfunction

Background. Nanoparticle-mediated radiotherapy is a promising approach to enhance tumor radiosensitivity while reducing damage to healthy tissues. Particularly, melanoma is a highly aggressive malignancy with an increasing global incidence and limited therapeutic options in advanced stages, due to its intrinsic radioresistance and narrow therapeutic window in metastatic settings. In this study, we developed a systematic library of gadolinium-doped iron oxide nanoparticles (Fe-Gd NPs) with controlled compositions (0–75% Gd) to investigate the functional and compositional determinants of radiosensitization in melanoma. Methods. The physicochemical properties of the Fe-Gd NPs, including the morphology, crystallinity, and composition, were thoroughly characterized and correlated with biological responses. The biological evaluation was performed using both 2D and tissue-relevant 3D melanoma models, integrating metabolic viability assays (MTT/MTS), mitochondrial function (ATP quantification, MitoTracker analysis), and clonogenic survival following low-energy X-Ray irradiation (150 kV, 4 Gy). In vivo systemic tolerance and response in non-tumor tissues were investigated in BALB/C mice. Results. Our results showed that radiosensitization did not increase linearly with the Gd content, with the 25% Fe-Gd NPs being identified as a therapeutic window and having the most pronounced effect in melanoma cell models, while maintaining good systemic safety in vivo. This study provides functional evidence that nanoparticle-mediated radiosensitization is not only determined by a high Z content, but also by tumor-specific metabolic adaptability and the nanoparticle composition. Conclusions. These findings support the rational design of Fe-Gd nanoparticles with optimized therapeutic windows and highlight the importance of metabolic and 3D tissue-relevant models in preclinical evaluation of nanoparticle-mediated radiotherapy.