Acid responsive molybdenum (Mo)-based nanoparticles inhibit the cGAS-STING signaling pathway for sepsis therapy

Sepsis, an inflammatory disease caused by bacterial infection, has become a global public health crisis. Excessive reactive oxygen species (ROS) in sepsis patients act as the primary trigger for activating intracellular immune pathways, ultimately leading to multiple organ dysfunction syndrome. The overexpression of acidic metabolites and ROS, characteristic of the infected microenvironment, significantly impedes sepsis treatment. Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, plays a key role in inflammatory diseases. The detrimental effects of STING in sepsis have been well documented. Here, we developed a pH-responsive nanotherapy platform (DMSNM@C-178/PAA) that combines ROS scavenging with cGAS-STING pathway inhibition for anti-inflammatory therapy. This nanoparticle is selectively released in the infected microenvironment, where reduced molybdenum-based polyoxometalates (Mo-POM) efficiently neutralize toxic ROS <i>in vivo</i>, while C-178 selectively inhibits the cGAS-STING pathway, thereby attenuating the inflammatory response and preventing organ deterioration. <i>In vitro</i> and <i>in vivo</i> studies demonstrate that DMSNM@C-178/PAA treats sepsis by eliminating excess ROS and modulating autoimmune dysfunction <i>via</i> the cGAS-STING pathway, providing a novel therapeutic strategy for sepsis management.