Beyond dose enhancement: Multi-level nanoparticle strategies to overcome biological barriers of cancer radioresistance.

Radiotherapy is a cornerstone of oncological treatment; tumor radioresistance, driven by complex factors such as enhanced DNA repair, hypoxic tumor microenvironments, and cancer stem-like cells, frequently limits clinical efficacy. Nanoparticle-based radiosensitizers represent an emerging approach to addressing these challenges. These nanoplatforms can operate through multi-level mechanisms: (1) physical enhancement via increased local energy deposition and secondary electron generation from high-Z materials such as gold and hafnium oxide; (2) chemical enhancement through localized amplification of reactive oxygen species (ROS); and (3) biological resensitization through modulation of DNA repair, pro-survival signaling, and, in selected systems, the tumor microenvironment and antitumor immune responses. This article presents a comprehensive overview of the biological basis of radioresistance and critically evaluates recent advances in nanoparticle radiosensitizers, including metallic, metal oxide, polymeric, and surface-functionalized platforms. We discuss current preclinical evidence, activation of cGAS-STING signaling in selected nanoparticle systems, and barriers to clinical translation. We highlight the potential of multifunctional nanoparticles to enable precision radiosensitization by addressing specific biological vulnerabilities associated with resistant tumors.