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

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.