A dual-functional, responsive nanomodulator alleviates pyroptosis-associated lung injury in ARDS by selectively suppressing the cGAS–STING signaling axis

Injury and inflammation mediated by pulmonary endothelial cell pyroptosis are crucial factors in the progression of acute respiratory distress syndrome (ARDS). Although blocking the cyclic GMP‒AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway is a promising strategy for inhibiting the activation of the NLRP3 inflammasome and GSDMD-induced pyroptosis, current therapeutic options remain limited because of poor bioavailability and insufficient lung‑specific targeting of STING inhibitors. Here, we engineered a reactive oxygen species (ROS)-responsive Prussian blue hybrid nanoplatform (LPBSN@T) for targeted delivery of the STING inhibitor SN-011. When functionalized with a lung endothelial cell-targeting peptide (LET), LPBSN@T enables efficient pulmonary accumulation. Under the responsive cleavage of thioketal (TK), LPBSN@T precisely releases SN-011, which competitively binds to STING, thus reducing the levels of phosphorylated STING, TBK1, and IRF3. Moreover, the exposed Prussian blue framework scavenges ROS and mitigates mitochondrial DNA (mtDNA) release, thereby synergistically suppressing the cGAS‒STING‒NLRP3 pathway. Overall, the LPBSN@T nanoplatform significantly reduced caspase-1 activation and gasdermin D (GSDMD) cleavage, inhibited pyroptosis, and attenuated cytokine storms, ultimately alleviating lipopolysaccharide (LPS)-induced ARDS. This synergistic strategy, which combines cGAS‒STING blockade with oxidative stress correction, offers a novel therapeutic paradigm for the treatment of ARDS.