Molecular Etching‐Derived High‐Brightness NIR‐II Gold Nanoclusters for High‐Resolution Bioimaging and Photothermal Therapy

Abstract Glutathione‐capped gold nanoclusters (GSH‐Au NCs) with second near‐infrared (NIR‐II, 1000–1700 nm) fluorescence have received increasing interest in biomedical applications. However, conventional aqueous synthesis of GSH‐Au NCs results in low NIR‐II absolute fluorescence quantum yield (≈0.27%) and limited renal clearance efficiency (≈70%), which restricts its clinical applications. This study reports a GSH‐etching post‐synthesis method to selectively convert nonfluorescent GSH‐Au n NCs ( n > 25) into fluorescent GSH‐Au 25 NCs (eGSH‐Au NCs). This molecular etching process decreases the size of the NCs from 3.3 to 2.0 nm and afforded 37% increase in NIR‐II absolute fluorescence quantum yield and 11.9% enhancement in renal clearance efficiency. The optimized eGSH‐Au NCs facilitates whole cerebrovascular imaging through the scalp and skull, tumor vasculature imaging with a resolution of 40.8 µm, dynamic tumor perfusion imaging with a signal‐to‐background ratio of 10.5, and enhanced lymphatic vessel and lymph node imaging. Additionally, eGSH‐Au NCs exhibit superior photothermal properties, achieving almost 100% tumor growth inhibition in Hepa1‐6 tumor‐bearing mice. This study presents a novel strategy to improve the bioimaging and therapeutic performance of NIR‐II Au NCs, thus advancing their clinical translation.