Theranostic Gold Nanoparticles Encapsulated in a PEGylated Liposome as an Effective Radiosensitizer for Cancer Radiation Therapy

High-Z materials enhance radiation dose deposition primarily through strong photoelectric absorption. Leveraging this property, nanoparticles based on high-Z content materials can be utilized as nanoscale radiosensitizers to enhance the efficacy of radiotherapy. Notably, gold nanoparticles (Au: gold, AuNPs) have been intensively investigated due to their excellent radiosensitizing effect and straightforward synthesis process. However, without additional modifications, they suffer from unfavorable biodistribution and inefficient tumor targeting, which limit their efficacy as radiosensitizers. Herein, we developed ultrasmall AuNPs encapsulated in PEGylated liposome (PEG: polyethylene glycol, Au-Lipo) and optimized their PEGylated lipid composition to improve their performance as radiosensitizers. Au-Lipo formulation was synthesized and optimized to exhibit good stability and cellular uptake <i>in vitro</i>. Au-Lipo demonstrated a dose enhancement factor at 2 Gy (DEF_2Gy) of 2.56 which tends to have higher value compared to the commercial AuNPs, AuroVist. Furthermore, Au-Lipo showed substantial tumor uptake in positron emission tomography with significantly improved tumor therapeutic efficacy compared to radiotherapy alone in 4T1 tumor-bearing mice (<i>P</i> = 0.035). These results suggest that Au-Lipo is a promising radiosensitizing agent, offering systemic injectability, enhanced tumor-targeting efficiency, and significant therapeutic potential for improving radiotherapy outcomes.