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

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Lung cancer remains a leading cause of cancer-related mortality worldwide.
• Sonodynamic therapy (SDT) efficacy is often limited by tumor hypoxia and abnormal vasculature.
• There is a critical need for advanced therapeutic strategies to overcome these challenges.

Purpose of the Study:

• To develop and evaluate manganese-containing DNA nanoflowers (DHA-DDF) loaded with doxorubicin (DOX) for enhanced sonodynamic therapy (SDT).
• To functionalize DHA-DDF with AS1411 aptamer and a hypoxia-inducible factor-1α (HIF-1α) antisense sequence to target lung cancer.
• To investigate the in vitro and in vivo efficacy of the combined SDT and drug delivery system against Lewis lung carcinoma (LLC).

Main Methods:

• Synthesis and characterization of AS1411- and HIF-1α antisense-functionalized, doxorubicin-loaded manganese DNA nanoflowers (DHA-DDF).
• In vitro evaluation of DHA-DDF stability, pH-responsive drug release, and effects on LLC cells (apoptosis, migration, invasion, HIF-1α, VEGF expression).
• In vivo assessment of DHA-DDF accumulation, tumor penetration, and therapeutic efficacy in a subcutaneous LLC mouse model treated with ultrasound.

Main Results:

• In vitro studies confirmed DHA-DDF stability and pH-responsive doxorubicin release, leading to apoptosis and inhibited migration/invasion of LLC cells.
• DHA-DDF combined with ultrasound treatment effectively downregulated HIF-1α and VEGF expression in LLC cells.
• In vivo studies demonstrated enhanced tumor targeting and penetration of DHA-DDF, significantly reducing tumor growth and extending survival in mice.
• The combined approach suppressed hypoxia-related gene expression, inhibited proliferation, and blocked tumor angiogenesis.

Conclusions:

• Programmable, biocompatible, and multifunctional DNA nanoflowers significantly improve SDT efficacy for lung cancer.
• This nanoplatform provides robust tumor inhibition in both cellular and animal models.
• DNA nanotechnology holds considerable potential for developing innovative and effective cancer therapies.