EUK nanozyme-loaded PL&GA coacervate droplets attenuate ulcerative colitis through restoring gut homeostasis and restricting intestinal cell ferroptosis

Ulcerative colitis (UC), a prevalent form of inflammatory bowel disease (IBD), manifests as chronic diarrhea, abdominal pain, and bloody mucoid stools. Current treatment approaches for UC are typically limited by inadequate targeted delivery, premature gastrointestinal degradation, and systemic off-target effects. To address these challenges, we engineered PL&GA@EUK, EUK-134 nanozymes encapsulated in polylysine (PL) and glycyrrhizic acid (GA) coacervate droplets. PL&GA@EUK exhibited potent superoxide dismutase- and catalase-mimetic activities, scavenging hydroxyl radicals and demonstrating anti-inflammatory efficacy in both <i>in vivo</i> and <i>in vitro</i> models. In mice with dextran sulfate sodium-induced colitis, oral administration of PL&GA@EUK for 14 days significantly ameliorated the disease activity index and colonic damage. By maintaining the integrity of the intestinal mucosal barrier and modulating redox homeostasis, it protects the intestinal epithelial cells against ferroptosis, ultimately attenuating colitis progression. 16S rDNA sequencing revealed that PL&GA@EUK significantly enriched beneficial commensals, while suppressing opportunistic pathogens. Metabolomic analysis further indicated that it modulates lipid peroxidation-associated metabolites by regulating the biosynthesis of polyunsaturated fatty acids. Crucially, PL&GA@EUK achieved enhanced colon-targeted delivery with minimal systemic toxicity, thereby overcoming the key limitations of conventional treatments. The multifaceted mechanism of PL&GA@EUK, involving reactive oxygen species scavenging, gut microbiome remodeling, and ferroptosis suppression, underscores its immense promise for the clinical management of IBD.