A DNA damage-amplifying nanoagent for cancer treatment via two-way regulation of redox dyshomeostasis and downregulation of tetrahydrofolate

DNA damage-based therapy is widely used in cancer treatment, yet its therapeutic efficacy is constrained by the redox homeostasis and DNA damage repair mechanisms of tumor cells. To address these limitations and enhance the efficacy of DNA damage-based therapy, HA-CuH@MTX, a copper-histidine metal-organic complex (CuH) loaded with methotrexate (MTX) and modified with hyaluronic acid (HA), was developed to amplify the DNA damage induced. In vitro experiments demonstrated that the presence of both Cu + and Cu 2+ in HA-CuH@MTX enables two-way regulated redox dyshomeostasis (RDH), achieved through Cu + -catalyzed generation of •OH and Cu 2+ -mediated consumption of glutathione, thereby facilitating efficient DNA oxidative damage. In addition, DNA damage repair is synergistically inhibited by impairing nucleotide synthesis via histidine metabolism and MTX downregulation of tetrahydrofolate, a crucial raw material in nucleotide synthesis. In vivo experiments with 4T1 tumor-bearing mice demonstrate 83.6 % inhibition of tumor growth by HA-CuH@MTX. This work provides a new strategy to amplify the DNA damage caused by DNA damage-based cancer therapies, and holds great potential for improving their therapeutic efficacy.