Dual-Enzyme Nanoassemblies of Carbon Dots and Gold for Tumor Microenvironment-Responsive Immunotherapy in Hepatocellular Carcinoma

Nucleolar redox homeostasis, which is the balance between oxidants such as H 2 O 2 and reductants such as glutathione (GSH) within mitochondria and is vital for numerous biological processes, including biosynthesis and apoptosis, is a promising target for cancer therapy. Herein, we report nucleolus-targeted core–shell structured oxidative stress amplifier ECAu@CD NPs, which consisted of a nanoshell assembled from a carbon dot-based nanozyme, encapsulating a nanocore composed of the natural product cordycepin (Cor), plant polyphenol epigallocatechin 3-gallate (EGCG), and chloroauric acid (HAuCl 4 ). We observed that the ECAu@CD NPs can specifically target the nucleous and deplete mitochondrial glutathione in an atomically efficient manner, thereby amplifying the reactive oxygen species damage induced by EGCG and ultimately triggering apoptosis in cancer cells. Our research indicates that the targeted injection of these particles, guided by imaging, significantly curbs the progression of tumors in subcutaneous xenograft models of hepatocellular carcinoma, all while maintaining safety and avoiding any adverse reactions. Specifically, the amplifier recruited massive tumor-infiltrating immune cells, such as T cells, NK cells, and macrophages, thus transforming “cold” tumors into “hot” ones to activate systemic antitumor immune responses. In summary, our investigation reveals that ECAu@CD NPs enhance oxidative stress within the cell nucleus and effectively inhibit tumor growth in vivo, emerging as a strong candidate for anticancer therapy.