Synthesis and Characterization of Copper‐Crosslinked Carbon Dot Nanoassemblies for Efficient Macrophage Manipulation

Nanomedicines loaded in macrophages (MAs) can actively target tumors without dominantly relying on the enhanced permeability and retention (EPR) effect, making them effective for treating EPR‐deficient malignancies. Herein, copper‐crosslinked carbon dot clusters (CDCs) are synthesized with both photodynamic and chemodynamic functions to manipulate MAs, aiming to direct the MA‐mediated tumor targeting. First, green fluorescent CDs (g‐CDs) are prepared by a one‐step hydrothermal method. Subsequently, the g‐CDs are complexed with divalent copper ions to form copper‐crosslinked CDCs (g‐CDCs/Cu), which are incubated with MAs for their manipulation. Experimental results revealed that the prepared g‐CDCs/Cu displayed good aqueous dispersibility and fluorescent emission properties. The nanoassemblies can be activated to deplete the overexpressed glutathione (GSH) and generate reactive oxygen species (ROS) in the presence of laser irradiation through the combined Cu‐mediated chemodynamic therapy and CD‐mediated photodynamic therapy. Furthermore, the ROS produced in MAs enabled polarization of MAs to antitumor M1 phenotype, suggesting the future potential use to reverse the immunosuppressive tumor microenvironment. These results obtained from the current study suggest a significant potential to develop g‐CDCs/Cu for GSH depletion, ROS generation, and MA M1 polarization as a theransotic agent to tackle cancer. Cu(II)‐crosslinked green fluorescent carbon dot nanoclusters are synthesized to show monodispersibility and tumor microenvironment‐responsive dissociation, and demonstrate abilities of GSH depletion, ROS generation, and singlet oxygen generation under laser irradiation. The nanoclusters can be taken up by macrophages to induce intracellular ROS generation and M1 phenotype polarization, which is desired for further biomedical applications.