Ultrasmall Au 10–12 Nanoclusters: A Novel Platform for 223 Ra‐Targeted Tumor α‐Therapy

ABSTRACT 223 Ra, a potent α‐emitting radionuclide, is currently limited to treating bone metastases in clinical practice. This constraint stems from the lack of stable chelating agents capable of withstanding its high recoil energy and the five decay daughters produced during decay, hindering its application in targeted α‐therapy (TAT). Ultrasmall gold nanoclusters (AuNCs) exhibit favorable pharmacokinetics, featuring tunable blood half‐life, renal clearance, and low hepatic/splenic sequestration. Given gold's high atomic number and structural flexibility, we hypothesized that AuNCs could encapsulate 223 Ra and its decay progeny, serving as an effective carrier for tumor TAT. Density functional theory simulations revealed that Au 10–12 nanoclusters, particularly a catenane‐structured Au 10 , could incorporate 223 Ra and its daughters with favorable energy dynamics. We then engineered α v β 3 ‐targeted AuNCs co‐labeled with 223 Ra and 68 Ga ( 68 Ga/ 223 Ra@AuNCs‐RGD). Molecular docking confirmed receptor specificity, while in vitro and in vivo studies demonstrated tumor‐specific targeting. PBPK modeling and Monte–Carlo simulations showed prolonged circulation ( t 1/2β = 139.4 min), renal clearance, sustained tumor retention, and efficient tumor energy deposition. The 68 Ga/ 223 Ra@AuNCs‐RGD platform achieved complete tumor regression and stimulated antitumor immunity, suggesting potential for TAT–immunotherapy synergy. This study establishes a theoretical foundation for stably doping 223 Ra into gold clusters and provides a framework for developing novel 223 Ra‐based α‐radiopharmaceuticals with significant clinical translation potential.