Sonodynamic Therapy-Based DNA Nanocarriers with Hypoxia-Inducible Factor-1α Silencing Activation for Precision Lung Cancer Therapy

As lung cancer is still the deadliest cancer worldwide, there is an urgent need for safer and more efficient therapies. This study aims to address the challenges posed by tumors in reducing the efficacy of sonodynamic therapy (SDT) through mechanisms such as hypoxia and abnormal blood vessel formations. In this study, manganese-containing DNA nanoflowers (DHA-DDF) loaded with doxorubicin (DOX) were functionalized with an AS1411 aptamer and a hypoxia-inducible factor-1α (HIF-1α) antisense sequence. The in vitro tests confirmed their stability and pH-responsive drug release properties. The combined treatment of DHA-DDF and ultrasound could induce apoptosis, inhibit the migration and invasion of Lewis lung carcinoma (LLC) cells, and down-regulate the expression of HIF-1α and VEGF in LLC cells. The in vivo studies using subcutaneous LLC in mice showed that ultrasound enhanced the tumor-targeted accumulation and penetration of DHA-DDF. The combined approach markedly reduced tumor development and extended the survival of tumor-bearing mice, effectively down-regulated the expression of hypoxia-related genes, inhibited cell proliferation, and blocked tumor angiogenesis. The programmable, biocompatible, and multifunctional nanoflowers demonstrate a notable improvement in the efficacy of SDT and provide robust tumor inhibition in both cellular and animal models. The findings highlight the potential of DNA nanotechnology in advancing innovative cancer therapies.