Macrophage-Targeted Nanocarriers Based on Tetrahedral DNA Nanostructure Alleviate Sepsis-Induced Acute Lung Injury by Triple-Pathway Suppression of Pyroptosis.
Zhang Yunlong, Pan Mingliang, Ma Fei, He Changting, Gu Qin, Wang Yongli, Pan Zhou, Wang Huijuan, Yan Yan, Fu Xinting, Jia Yue, Duan Han, Wu Yanqiu, Wei Zihui, Wang Jiamei, Li Bin, Liao Yuhui, Zhan Liying
Abstract
Sepsis-induced acute lung injury (SI-ALI) is a critical complication of sepsis characterized by severe pulmonary edema, hyper-inflammatory responses, and high mortality rates, for which precise therapeutic strategies remain limited. In this study, we developed a macrophage-targeting, dimethyl fumarate (DMF)-loaded tetrahedral DNA nanoplatform (T-D@TDN) and evaluated its physicochemical properties, antipyroptotic mechanisms, and therapeutic efficacy in SI-ALI. The nanostructure exhibits excellent biocompatibility, efficient alveolar macrophage (AM) targeting, and prolonged pulmonary retention following intranasal administration. In a murine model of SI-ALI induced by cecal ligation and puncture (CLP), T-D@TDN treatment significantly reduced pulmonary inflammatory cytokine levels and alleviated pulmonary edema and tissue injury, accompanied by a marked improvement in the 48-h survival rate. Mechanistically, T-D@TDN integrates a triple-regulation strategy to suppress pyroptosis: the TDN framework exerts intrinsic ROS-scavenging activity, while the released DMF activates the NRF2/HO-1 axis to further eliminate intracellular ROS and directly inhibits GSDMD cleavage. Collectively, these findings demonstrate that T-D@TDN functions as a multifunctional inhalable nanotherapeutic agent capable of multidimensionally regulating oxidative stress and pyroptosis pathways, providing a promising noninvasive strategy for the treatment of SI-ALI and related inflammatory lung diseases.
Key Findings
- Developed a macrophage-targeting, dimethyl fumarate-loaded tetrahedral DNA nanoplatform (T-D@TDN) with excellent biocompatibility and efficient alveolar macrophage targeting.
- T-D@TDN treatment significantly reduced pulmonary inflammatory cytokines, alleviated pulmonary edema and tissue injury, and improved 48-hour survival in a murine sepsis-induced acute lung injury model.
- Mechanistically, T-D@TDN suppresses pyroptosis via triple pathways: intrinsic ROS scavenging by the DNA nanostructure, activation of the NRF2/HO-1 axis by DMF to eliminate intracellular ROS, and direct inhibition of GSDMD cleavage.
Clinical Significance
This study presents a promising inhalable nanotherapeutic strategy that multidimensionally regulates oxidative stress and pyroptosis, offering a novel noninvasive treatment approach for sepsis-induced acute lung injury and related inflammatory lung diseases.
Citation
Zhang Yunlong, Pan Mingliang, Ma Feiet al.. Macrophage-Targeted Nanocarriers Based on Tetrahedral DNA Nanostructure Alleviate Sepsis-Induced Acute Lung Injury by Triple-Pathway Suppression of Pyroptosis. ACS applied materials & interfaces. 2026-Apr-06.