Atomically-precise Au(Lys-Cys-Lys) nanoclusters for radiation sensitization.

Radiotherapy is a leading method for cancer treatment, effectively eliminating cancer cells but often causing collateral damage to surrounding healthy tissue. Radiosensitizers aim to enhance the therapeutic effects of radiotherapy while minimizing harm to normal cells. We recently reported atomically-precise gold nanoclusters, Au(Lys-Cys-Lys), synthesized via a photochemical method coupled with a novel accelerated size-focusing procedure. These nanoclusters exhibit a distinct luminescence emission profile, reflecting exceptional optical purity and the absence of contamination from other nanocluster species. They demonstrate efficient oxygen radicals generation under light irradiation. In this study, we comprehensively evaluated the radiosensitization potential of Au(Lys-Cys-Lys) nanoclusters in vitro and in vivo, alongside their pharmacokinetics, biodistribution and toxicity. The nanoclusters demonstrated high stability under physiological conditions and efficient internalization in tumor cells, achieving dose enhancement factors of 2.0 and 1.6 in KB and 4T1 tumor cells, respectively, under 225 kVp X-ray irradiation. Mechanistic investigations revealed enhanced radiation-induced DNA damage and disruption of DNA repair pathways. The radiosensitizing effects were further validated in radioresistant pancreatic ductal adenocarcinoma cells using the clonogenic assay and γH2AX analysis of double-strand breaks, as well as in a duck chorioallantoic membrane model. With ultra small size (~ 1.7 nm) and favorable surface framework, the nanoclusters exhibited relevant pharmacokinetics (circulation half-life, t₁₂ = 10.4 h) and renal clearance. In a KB tumor-bearing mouse model, Au(Lys-Cys-Lys) significantly delayed tumor progression and prolonged survival under 8 Gy irradiation without observed side-effects. These findings establish Au(Lys-Cys-Lys) nanoclusters as a potentially translatable radiosensitizer, advancing cancer radiotherapy strategies.