Dual delivery of agmatine and microRNA-126b using agmatine-mediated DNA nanotube assemblies for acute lung injury therapy.

Acute lung injury (ALI) is characterized by widespread inflammation and oxidative stress, leading to impaired gas exchange and significant morbidity. In this study, we propose a potential approach using a magnesium-free DNA self-assembly strategy to assemble a DNA nanotube that carries agmatine and microRNA-126b mimics (NT^AGM-126). Agmatine not only reduces electrostatic repulsion between DNA helices, thereby facilitating the folding of the DNA nanotube, but also serves as a drug that inhibits iNOS signaling. The microRNA-126b mimics restore the downregulated microRNA-126b in macrophages and suppress inflammation by targeting high mobility group box 1 (HMGB1). Preliminary results indicated that agmatine can effectively facilitate the assembly of the DNA nanotube, improve serum stability, and enhance the cellular uptake efficiency of NT^AGM-126. Further in vitro and in vivo results demonstrate that NT^AGM-126 effectively reduces oxidative stress and inflammation by downregulating iNOS and HMGB1, providing a combined therapeutic effect in ALI. This study highlights the potential of agmatine-facilitated DNA nanostructures as a versatile drug delivery platform for treating inflammatory diseases, broadening the application of DNA nanotechnology in biomedical research. STATEMENT OF SIGNIFICANCE: This study introduces a promising therapeutic approach using a magnesium-free DNA self-assembly strategy to create a DNA nanotube (NT^AGM-126) that carries agmatine and microRNA-126b mimics. The agmatine not only aids in the assembly and stability of the DNA nanotube but also inhibits iNOS signaling, while the microRNA-126b mimics restore downregulated microRNA-126b in macrophages and suppress inflammation by targeting HMGB1. Preliminary and further results demonstrate that NT^AGM-126 effectively reduces oxidative stress and inflammation, providing a combined therapeutic effect in ALI. This study underscores the potential of agmatine-facilitated DNA nanostructures as a versatile drug delivery platform, broadening the application of DNA nanotechnology in the treatment of inflammatory diseases and advancing biomedical research.