Coordination and Click Chemistry Dual-Driven Self-Assembled Copper-DNA Nanoparticles for Tumor Imaging and Therapy

Metal ions coordination-driven self-assembly technique has emerged as a highly promising strategy in the field of DNA nanomaterials for constructing structurally defined and functionally tailored molecular materials. However, the instability of DNA-based nanomaterials remains a critical challenge that severely hinders their practical applications. Herein, we propose a new strategy for the construction of stable copper-DNA nanoparticles (CDCN) via a dual-driven self-assembly process synergistically mediated by coordination chemistry and click chemistry. The simplicity and broad applicability of this assembly method were enabled by the use of alkyne- and azide-modified DNA in conjunction with Cu(I) ions. The triazole linker generated via the Cu-catalyzed alkyne-azide cycloaddition (CuAAC) reaction is capable of coordinating with Cu ions, a synergistic interaction that effectively confers robust structural stability to copper-DNA nanoparticles (CDCN). Importantly, by leveraging this dual-driven assembly method, we successfully constructed stable, 4T1-targeted CDCN nanomaterials (denoted as CDCN-4T1) by employing the aptamer sequence of 4T1 breast cancer cells and Cu(I) ions. Owing to the presence of redox-active Cu ions, CDCN-4T1 nanoparticles can trigger a Fenton-like reaction within the tumor microenvironment to generate reactive oxygen species (ROS), thereby enabling effective chemodynamic therapy (CDT) against tumor cells. Furthermore, excessive copper ion intake will be highly accumulated in mitochondria, leading to energy metabolism disorders and thus destroying tumor cells. In vivo studies demonstrated that intravenously administered CDCN-4T1 nanoparticles specifically targeted tumors in 4T1 breast cancer-bearing BALB/c mice, exhibiting potent CDT efficacy and copper-dependent immunogenic cell death-mediated immunotherapy effects. Meanwhile, magnetic resonance imaging (MRI) was performed to confirm the effective treatment of CDCN-4T1. This approach will advance the fields of DNA nanotechnology in tumor diagnosis and therapy.