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

Yue Chen; Di Wu; Quan Li; Zhenghua Wei; Qian Liu; Jin Li; Daohui Gong; Chaowang Huang; Qianyi You; Hang Qian; Guansong Wang

doi:10.1016/j.mtbio.2025.101760

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

Mater Today Bio. 2025 Apr 11:32:101760. doi: 10.1016/j.mtbio.2025.101760. eCollection 2025 Jun.

Authors

Yue Chen^{1

2

3}, Di Wu^{1

4}, Quan Li^{1

2

3}, Zhenghua Wei^{1

2

3}, Qian Liu⁵, Jin Li^{1

2

3}, Daohui Gong^{1

2

3}, Chaowang Huang^{1

6}, Qianyi You^{1

6}, Hang Qian^{1

2

3}, Guansong Wang^{1

2

3}

Affiliations

¹ Department of Pulmonary and Critical Care Medicine, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
² Chongqing Key Laboratory of Precision Medicine and Prevention of Major Respiratory Diseases, Third Military Medical University, Chongqing, 400037, China.
³ Key Laboratory of Respiratory Disease Research at Universities in Chongqing, Third Military Medical University, Chongqing, 400037, China.
⁴ Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China.
⁵ Laboratory of Pharmacy and Chemistry, and Laboratory of Tissue and Cell Biology, Lab Teaching & Management Center, Chongqing Medical University, Chongqing, 400016, China.
⁶ Department of Geriatrics and Special Services Medicine, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.

Abstract

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.

Keywords: ALI/ARDS; Aminoguanidine; DNA nanostructure; Self-assembly.