Great efforts have been devoted to the exploration of potential diagnostic and therapeutic applications of thiolate-protected gold nanoclusters (Au NCs). One of the therapeutic applications is the photosensitized generation of highly reactive singlet oxygen (1O2) using Au NCs for photodynamic therapy. However, there is scope for improving the 1O2-generation efficiency of Au NC photosensitizers. In this study, we exploit three strategies to improve the 1O2-generation efficiency of glutathione-protected Au NCs: (i) doping with silver (i.e., using bimetallic AuAg NCs, (ii) achieving aggregation-induced emission (AIE) using a Au­(I)–thiolate complex, and (iii) achieving self-assembly-induced emission (SAIE) using a polymer nanogel. The combination of these three effects dramatically increased the 1O2-generation efficiency and enhanced the luminescence of the glutathione-protected Au NCs, owing to the inhibition of the nonradiative decay pathways. Finally, the photosensitizers based on AuAg NC@nanogel composites were successfully used for antimicrobial photodynamic therapy (a-PDT) against oral bacteria. This study provides general insights into the molecular design of water-soluble Au NC photosensitizers for therapeutic applications.

The production of reactive oxygen species (ROS) by ultrasonic activation of nanomaterials has great potential in sonodynamic therapy and sonocatalysis. Herein, we first demonstrate that watersoluble Au 25 (Captril) 18 nanoclusters (NCs) can work as a sonosensitizer to produce singlet oxygen ( 1 O 2 ) under ultrasound irradiation. The ultrasonically mediated 1 O 2 production was also confirmed in other thiolated Au NCs, including those protected by glutathione or 6-aza-2thiothymine (ATT). There are two possible pathways to ultrasonically excite the thiolated Au NCs via microbubble cavitation: (i) sonoluminescence from water and (ii) ROS production (hydroxyl radical) by pyrolysis cleavage of water. We suggest that the sonoluminescence from water could excite the Au NCs to produce 1 O 2 under ultrasonication, when there is a spectral overlap between the sonoluminescence and the absorption of Au NCs to allow energy transfer. The ultrasonic excitation of ATT-Au NCs was confirmed by the observation of sonoluminescence. The Au(I)-SR shell of thiolated Au NCs is responsible for generating the triplet state of thiolated Au NCs to produce 1 O 2 under ultrasonication. As thiolated Au NCs also have photosensitizing capability, it would be used as ROS-based nanomedicine for a sonodynamic and/or photodynamic therapy.