Radiotherapy Enhancement by Gold Nanocluster‐functionalized Nanoliposomes Using Polychromatic Orthovoltage X‐ray Irradiation

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, as the most effective chemoradiation therapies achieve unsatisfactory outcomes while associated with high toxicity. Nanoliposomal drug delivery systems are widely used to improve chemotherapy safety, yet passive release of amphiphilic drugs may still associate with adverse toxicity. To address this, we previously developed nanoliposomes functionalized with hydrophobic gold nanoclusters, demonstrating radiocatalytic activity and enhanced chemoradiotherapy effects in 3D PDAC microtumors under synchrotron irradiation. In this study, gold nanocluster‐functionalized nanoliposomes (AuLPs) were optimized and evaluated under 220 kVp orthovoltage X‐ray irradiation, widely used in preclinical irradiation systems. AuLPs containing 0.2 mol% gold nanoclusters produced 1.5‐fold more reactive oxygen species than unloaded liposomes. However, molar ratios above 0.5 mol% and continuous presence of liposomes during irradiation were necessary to improve radiotherapy outcomes in 3D PDAC microtumor models following 4 and 8 Gy irradiation. Pharmacokinetics and biodistribution evaluations showed a modest increase in tumor gold content 24 h post‐injection in orthotopic PDAC models. Altogether, these results underscore the potential of gold‐radiotherapy‐responsive liposomes while highlighting critical formulation challenges, which must be resolved for full therapeutic potential.