DNA nanodevice as a multi-module co-delivery platform for combination cancer immunotherapy

Area of Science:

• Biotechnology
• Cancer Research
• Immunology

Background:

• Cancer immunotherapy faces challenges in delivering multiple immune stimulators to overcome the immunosuppressive tumor microenvironment (TME).
• Efficient delivery systems are crucial for enhancing anti-tumor immune responses and reprogramming the TME.

Purpose of the Study:

• To develop a DNA nanodevice for efficient co-delivery of multiple immunomodulators.
• To enhance cancer immunotherapy by reprogramming the TME and eliciting a robust anti-tumor response.

Main Methods:

• Assembled a DNA nanodevice incorporating doxorubicin (Dox), double-stranded DNA (dsDNA), interleukin-12 (IL-12), and small hairpin programmed cell death-ligand 1 (shPD-L1) transcription templates.
• Utilized cyclo[Arg-Gly-Asp-(d-Phe)-Cys] (cRGD) peptides for targeted delivery and disulfide bonds for glutathione (GSH)-triggered release.
• Investigated the nanodevice's effect on tumor cell death, antigen-presenting cell (APC) activation, immune cell infiltration, and TME modulation.

Main Results:

• Dox induced immunogenic cell death (ICD) and enhanced APC phagocytosis.
• dsDNA activated stimulator of interferon genes (STING) signaling in APCs.
• The nanodevice promoted CD8+ and CD4+ T cell infiltration, creating an inflamed TME and enhancing immunotherapy effectiveness.
• Demonstrated significant inhibition of tumor growth and prevention of lung metastasis without obvious systemic toxicity.

Conclusions:

• The developed DNA nanodevice is a promising strategy for cancer combination therapy.
• This approach effectively reprograms the TME and enhances anti-tumor immunity.
• The nanodevice offers a potential solution for efficient and targeted cancer treatment with reduced systemic toxicity.