Arginine Polymerization Boosts Anti‐Inflammatory Effects and DNA Nanostructure‐Assisted siRNA Delivery in Acute Respiratory Distress Syndrome

Severe lung inflammation and acute respiratory distress syndrome (ARDS) represent one of the most life-threatening conditions in critical care units and no effective drugs are available clinically. Here, we show that the polymerization of arginine greatly boosts the anti-inflammatory effect of arginine in vitro. RNA transcription sequencing and analysis indicated that polyarginine upregulated the expression of the anti-inflammatory cytokine IL-4. Meanwhile, polyarginine can assemble DNA nanostructures in a magnesium-free manner and enhance the cellular uptake of DNA due to its cell-penetrating nature, thereby boosting DNA nanostructure-based drug delivery efficiency. To validate the potential of polyarginine as an anti-inflammation prodrug, an arginine trimer (3R) assembled DNA nanotube that carries p65 siRNA (NT^3R-p65) was assembled as a model nanomedicine for ARDS therapy. Flow cytometry results showed polyarginine-assembled DNA nanotubes exhibited higher cellular uptake efficiencies than the magnesium-assembled counterpart. Most importantly, NT^3R-p65 effectively suppressed lung inflammatory in vitro and in ARDS mouse models. Mechanistically, 3R suppresses phosphorylated p65 expression and upregulates IL-4 signaling pathway while p65 siRNA directly silencing p65 expression. The prodrug 3R and p65 siRNA exhibited additive anti-inflammation effects in vitro and vivo. Collectively, the prodrug and gene therapy combination might offer a potential strategy for treating ARDS or other severe lung inflammation-related diseases.