DNA-templated synthesis of surface vacancy-rich bifunctional copper sulfide promotes phototherapy via gene regulation

The current photodynamic performance of CuS nanoparticles (CuS NPs) alone is still greatly challenged by the low quantum yield of reactive oxygen species (ROS). At the same time, the efficiency of photothermal therapy (PTT) and photodynamic therapy (PDT) is reduced due to the self-protective ability of tumor cells when attacked by hyperthermia and ROS. To address this issue, we synthesized DCuxS NPs using customized DNA templates through a surface vacancy-rich engineering strategy. In addition to their inherent photothermal properties, the surface vacancy-rich of DCuxS NPs effectively hinders electron-hole pair complexation, thereby enhancing their photodynamic properties. Furthermore, the tumor-targeting NC3S aptamer and the i-motif DNA/Nrf2 siRNA chimera were attached to both ends of the DNA template. The final NDCuxS@siRNA NPs were highly enriched in tumor cells, while the i-motif undergoes a conformational change to release Nrf2 siRNA upon acidic stimulation for Nrf2 pathway blocking to decrease tumor cell protection effect against ROS and high temperature, creating a favorable tumor microenvironment for enhanced PTT and PDT effects. In this study, we explored the potential of DNA templates for engineering nanomaterials, enhanced the photodynamic properties of DCuxS NPs through a surface vacancy-rich strategy, and exploited the versatility of DNA templates to combine phototherapy with gene regulation, providing a promising approach for clinical tumor treatment.