Synergistic Targeting of Pyroptosis and cfDNA by 4-Octyl itaconate-Loaded ROS-Responsive Nanoparticles Attenuates Inflammatory Diseases

Pyroptosis-induced release of inflammatory factors and abnormally elevated levels of cell-free DNA (cfDNA) in inflammatory tissues are key drivers of inflammatory disease progression. Macrophages play a pivotal role in coordinating inflammatory immune responses, making their activity modulation crucial for treating inflammatory diseases. 4-Octyl itaconate (4-OI) exerts immunomodulatory effects by inhibiting macrophage pyroptosis, thereby reducing oxidative stress and inflammatory responses. Additionally, cationic nanoparticles demonstrate significant therapeutic advantages in inflammatory diseases due to their high affinity for cfDNA. Herein, we propose a combined therapeutic strategy employing ROS-responsive cationic nanoparticles to capture cfDNA while utilizing 4-OI release to reduce pyroptosis in inflammatory tissues, thereby remodeling the inflammatory microenvironment. This approach demonstrated excellent biocompatibility and efficacy in mouse models of inflammatory bowel diseases (including ulcerative colitis and Crohn's disease) and sepsis. The study reveals that this regimen exhibits low toxicity and substantial therapeutic potential, offering a novel treatment option for inflammatory diseases.