Gold Nanoclusters as Dual Agents for Engineering Tumor Vascular Leakiness and Performing Photothermal Therapy

Abstract Engineering nanomaterial‐induced endothelial leakiness (NanoEL) through tumor vasculature gaps allows for enhanced nanotherapeutics entry into tumors. However, current NanoEL strategies require two steps and multiple particle types: first with the NanoEL agent and subsequently with the therapeutics, thereby possibly increasing toxicity risks and complicating treatment protocols. Here, ultrasmall gold nanoclusters (AuNCs), Au 25 ( p ‐MBSA) 18 and Au 25 ( p ‐MBA) 18 are investigated as potential dual‐function NanoEL agents. These negatively charged, thiolate‐protected AuNCs induced endothelial leakiness in vitro without significant cytotoxicity, and the gaps retract in 30‒60 min after the AuNCs are removed. In vivo, AuNCs enhanced therapeutic delivery by inducing vascular leakiness and subsequently enabling photothermal therapy (PTT) to kill cancer cells after crossing the endothelial barrier. The tumors are significantly suppressed, if not eliminated, after AuNCs treatment with dosage of 0.1 mg kg −1 AuNCs and 10 min of near infrared irradiation, significantly better than the current PTT agents. The findings address key limitations of current tumor therapies strategies by offering an efficient, dual‐function approach that simplifies treatment protocols and improves therapeutic delivery.