Nanoparticle radiosensitizers in cancer radiotherapy: bridging preclinical promise and clinical reality.

Nanoparticle radiosensitizers have attracted considerable attention in radiation oncology owing to their capacity to enhance the therapeutic ratio of radiotherapy. Metal-based, biodegradable, and multifunctional composite nanoparticles exploit high atomic number elements to amplify local radiation dose deposition, generate reactive oxygen species, and modulate the tumor microenvironment. Preclinical studies have consistently demonstrated improved tumor control with reduced normal tissue toxicity across multiple experimental models. However, the trajectory from laboratory discovery to clinical adoption remains slow and platform-dependent. This critical review systematically examines the mechanistic landscape of nanoparticle radiosensitization, encompassing physical dose enhancement, oxidative stress-mediated damage, DNA repair interference, cell cycle modulation, hypoxia reversal, and immune activation. We then evaluate major nanoparticle classes through a translational lens, explicitly distinguishing platforms that have reached prospective clinical testing-most notably hafnium dioxide nanoparticles (NBTXR3/Hensify)-from those still confined to preclinical investigation. Key translational barriers are analyzed, including challenges in tumor-specific biodistribution, long-term toxicity, scalable manufacturing with batch consistency, and regulatory qualification. A comparative framework is provided to help readers assess the readiness level of different nanoplatforms. Rather than offering an exhaustive catalog of published studies, this review aims to identify critical roadblocks and prioritize research directions that can accelerate meaningful clinical deployment of nanoparticle radiosensitizers in cancer radiotherapy.