Macrophage-Targeted Nanocarriers Based on Tetrahedral DNA Nanostructure Alleviate Sepsis-Induced Acute Lung Injury by Triple-Pathway Suppression of Pyroptosis

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.