Dual-action ROS-responsive nanoparticles for synergistic suppression of pyroptosis and cfDNA in inflammatory bowel diseases

Pyroptosis-induced production of inflammatory cytokines and elevated levels of cell-free DNA (cfDNA) are major pathogenic drivers of intestinal inflammatory diseases. Inflammatory macrophages perform a vital role in mediating inflammatory immune responses, and their targeted modulation represents a promising therapeutic strategy for colitis. Cationic nanoparticles possess considerable therapeutic promise in inflammatory disorders due to their high affinity for cfDNA. In this work, we established a combinatorial therapeutic strategy using reactive oxygen species (ROS)-responsive cationic nanoparticles that simultaneously scavenge cfDNA and transport 4-octyl itaconate (4-OI), a potent agent against pyroptosis. This dual-functional nanosystem effectively rebalances the inflammatory microenvironment by suppressing pyroptosis and neutralizing cfDNA in colonic tissues. The nanoparticles exhibited excellent biocompatibility and robust therapeutic efficacy in the context of experimental IBD in mice, with sustained drug release triggered by ROS overexpression in inflamed regions. Notably, this approach demonstrates minimal cytotoxicity and leads to substantial amelioration of disease pathology, offering an innovative therapeutic approach for the targeted control of inflammatory diseases through the coordinated targeting of multiple pathological axes.