An epH-driven DNA nanodevice for impeding metastasis in vivo by selectively blocking cell signaling

Invasion and metastasis dominate tumor progression, causing a substantial proportion of cancer-related deaths. However, the efficacy of current antimetastatic treatments is hampered by the dearth of targeted therapeutics. Recently developed synthetic-receptor toolkits offer potential for artificially regulating cellular behavior. However, to the best of our knowledge, none has yet successfully suppressed tumor metastasis in vivo. Here, we report the first extracellular pH (epH)-driven DNA nanodevice for use in antimetastatic treatment in vivo by manipulating heterogeneous receptors on the tumor cell surface. This DNA nanodevice was constructed by partially locking tumorigenic receptor-specific aptamers with two i-motifs. Acidic extracellular pH induced dynamic allosteric reassembly within the nanodevice. The restructured nanodevice enabled oligomerization of c-Met and transferrin receptor, which inhibited tumor metastasis by blocking the hepatic growth factor (HGF)/c-Met signaling pathway. A suppressive efficacy of 86.25% was verified in an early hepatocarcinoma-pulmonary-metastasis mouse model. Such impressive antimetastatic efficacy suggests an efficient paradigm for developing adaptive antimetastatic therapeutics.