Aminoguanidine-assembled functional DNA tetrahedron alleviates acute lung injury by targeting the cGAS-STING signaling pathway

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) cause severe lung inflammation and damage, compromising respiratory function. Nanomedicine offers hope in controlling this inflammation. DNA nanostructures, as drug carriers, stand out due to their non-toxic, programmable, and precisely controllable traits. However, they face challenges in physiological stability and functionalization as carriers. Here, we introduce TET^AG, DNA tetrahedra assembled and functionalized with aminoguanidine without magnesium. Aminoguanidine not only aids tetrahedron assembly but also inhibits the cyclic GMP-AMP synthase and stimulator of interferon (cGAS-STING) pathway, a key inflammatory signal. By integrating STING siRNA into TET^AG (TET^AG-STING), we achieve synergistic anti-inflammatory effects in ALI/ARDS. Our results show that TET^AG offers improved stability and cellular uptake. Importantly, TET^AG-STING exhibits potent anti-inflammatory activity in vitro and in a Lipopolysaccharides-induced mouse model following intratracheal administration. This significantly improves the lung injury scores and pulmonary functions. These findings underscore aminoguanidine's therapeutic potential in ALI/ARDS and highlight the promise of DNA nanostructures in medical applications.