Tumor Radiosensitization with Gold Nanoparticles: Evolving Strategies To Improve Tumoral Gold Uptake and Catalyze Future Clinical Translation

Radiation therapy is integral to the treatment regimens of over 50% of cancer patients. However, it is not biologically targeted to just the tumor, leading to adverse effects in peritumoral normal tissue. Selective uptake of gold nanoparticles (AuNPs) by tumors realizes tumor-specific radiosensitization via increased secondary electron release from high atomic number gold atoms. Here, we review AuNP-mediated radiosensitization and outline strategies to optimize tumor-targeted AuNP delivery. Modifying the physicochemical characteristics of AuNPs, including size, shape, charge, and surface chemistry, can increase their ability to evade the reticuloendothelial system (RES) and penetrate the dense tumor stromal architecture, thereby promoting tumor accumulation. AuNPs of larger sizes readily accumulate peritumorally but are easily opsonized and cleared by the RES, whereas the smaller ones can passively internalize within tumor cells but are rapidly cleared by the kidneys. These contrasting size-dependent properties can be exploited through a size-switching strategy, whereby AuNPs reversibly aggregate or disaggregate in response to intrinsic tumor microenvironmental cues or extrinsic triggers, facilitating tumor uptake while remaining inert and RES-evasive in circulation. Stealth coatings on AuNPs like polyethylene glycol and zwitterions minimize opsonization and enhance RES evasion. Surface-functionalized AuNPs decorated with tumor-homing ligands boost selective uptake via tumor-specific receptors. Biomimetic membranes derived from native cells confer innate tumor-targeting capability and increase circulation time. These rationally designed AuNP platforms offers a promising pathway toward clinical translation.