Comprehensive insights into intracellular fate of WS2 nanosheets for enhanced photothermal therapeutic outcomes via exocytosis inhibition

Two-dimensional (2D) nanosheet (NS)-based photothermal agents (PTAs), such as transition-metal dichalcogenides, have shown immense potential for their use in cancer photothermal therapy (PTT). However, the nano-bio interaction study regarding these NS-based PTAs is stillin its infancy. In this study, we used WS2-PEG NS-based PTA as an example to provide comprehensive insights into the experimental understanding of their fate in cancer cells. The data revealed that three different endocytosis pathways (macropinocytosis, clathrin-dependent, and caveolae-dependent endocytosis), autophagy-mediated lysosome accumulation, and exocytosis-induced excretion contribute to the integrated pathways of WS2-PEG NSs within cells. These pathways are consistent with our previous reports on MoS2-PEG NS-based drug delivery platform, indicating that the composition difference of 2D NSs with PEGylation may have little influence on their intercellular fate. Moreover, by blocking the revealed exocytosis pathway-mediated secretion of WS(2)NSs in tumor cells, an effective approach is proposed to attain enhanced photothermal therapeutic outcomes with low doses of WS(2)NSs and under a low power of a near-infrared (NIR) laser. We expect that the exocytosis inhibition strategy may be a universal one for 2D NSs to achieve combination cancer therapy. This study may also provide more experimental basis for the future development of 2D NS's application in biomedicine (e.g. PTT).