Inflammatory bowel disease (IBD) is an autoimmune gastrointestinal disease characterized by chronic relapsing inflammation of the intestine. Excessive pyroptosis that exists in the inflamed intestine can activate damage signals and aggravate local inflammation in IBD. Here, we designed an oral pyroptosis nanoinhibitor, DXMS@CuM@PPADT@PSS (DCMP), which can target intestinal lesions, and respond to reactive oxygen species (ROS) to release active sites and drugs at the lesion. DCMP can inhibit the activation of the nucleotide-binding domain and leucine-rich repeat family pyrin domain containing 3 (NLRP3) inflammasomes by scavenging ROS, resulting in the down-regulation of gasdermin D (GSDMD) cleavage thus inhibiting pyroptosis. It also improved intestinal barrier function, decreased inflammatory cytokine levels, and increased the diversity of gut microbiota in mice with colitis. This work is believed to expand the biomedical application of nanomaterials for innate immunity modulation.