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Incorporating multiple molecular interactions within asystem to realize the metabolic reprogramming of cancer cells is prospected to be of great potential in cancer therapy. Herein, we report asupramolecular self-assembled DNAnanosystem, which reprogrammed the cellular antioxidant system via synergistic chemical and gene regulations.I nt he nanosystem, amphipathic telluroether was coordinated with Mn II to selfassemble into micelle,o nw hich as iNrf2 integrated DNA network was assembled. The great electron-donating capability of telluroether was revealed to greatly promote Mn II -based Fenton-like reaction to generate subversive COH in cancer cells. In response to adenosine triphosphoric acid, the siNrf2 was specially released in cytoplasm for down-regulating expression of detoxification enzymes,w hiche nhanced chemocatalysismediated oxidative stress in cancer cells,t hus significantly suppressing tumor progression.

Coupling materials chemistry systems to biological processes is a promising way to rationally modulate lysosomal functions. A proton‐driven dynamic assembly of a DNA nanoframework inside cells coupled with the lysosome‐mediated endocytosis pathways/lysosomal maturation, gives the rational modulation of lysosomal functions, which we term “lysosome interference”. Through lysosome‐mediated endocytosis, the DNA nanoframework with acid‐responsive semi‐i‐motif enters the lysosome and assembles into an aggregate in a process triggered by lysosomal acidity. The aggregate is suitable for long‐term retention. The consumption of protons resulted in lysosomal acidity reduction and hydrolase activity attenuation, thus hindering the degradation of nucleic acid drugs in the lysosome and improving gene silencing effects. This study shows a new way to achieve lysosome interference by coupling the subcellular microenvironment with a precisely programmable assembly system.

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