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

ABSTRACT 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.