Targeting HIF‐1α with Specific DNA Yokes for Effective Anticancer Therapy

Hypoxia, a ubiquitous hallmark in cancer, underscores the significance of targeting HIF‐1α, the principal transcriptional factor of hypoxic responses, for effective cancer therapy. Herein, DNA yokes, a novel class of DNA nanomaterials harboring specific HIF‐1α binding sequences (hypoxia response elements, HREs), are introduced as nanopharmaceuticals for cancer treatment. Comprising a basal tetrahedral DNA nanostructure and four HRE‐bearing overhanging chains, DNA yokes exhibit exceptional stability and prolonged intracellular retention. The investigation reveals their capacity to bind HIF‐1α, thereby disrupting its interaction with the downstream genomic DNAs and impeding transcriptional activity. Moreover, DNA yokes facilitate HIF‐1α degradation via the ubiquitination pathway, thereby sequestering it from downstream targets and ultimately promoting its degradation. In addition, DNA yokes attenuate cancer cell proliferation, migration, and invasion under hypoxic conditions, while also displaying preferential accumulation within tumors, thereby inhibiting tumor growth and metastasis in vivo. This study pioneers a novel approach to cancer therapy through the development of DNA‐based drugs characterized by high stability and low toxicity to normal cells, positioning DNA yokes as promising candidates for cancer treatment. Tetrahedral DNA nanostructures incorporating hypoxia response elements, termed as “HIF‐1α DNA yokes,” are synthesized as nanodrugs for cancer treatment. These HIF‐1α DNA yokes demonstrate efficient internalization into cancer cells and subsequent binding to HIF‐1α, triggering its degradation and concomitant inhibition of its transcriptional activity. These HIF‐1α DNA yokes show efficient anticancer ability bot in vitro and in vivo.