Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder characterized by intestinal inflammation, with frequent progression to complications including intestinal stenosis, obstruction, and perforation. The sustained inflammatory burden and gastrointestinal bleeding in IBD culminate in systemic iron depletion, predisposing patients to iron deficiency anemia (IDA). Here, we report a rationally engineered nanozyme, Radix Paeoniae Alba polysaccharide‑iron complexes (PPFeCs), designed to integrate superoxide dismutase-/catalase-mimicking antioxidase activities with bioavailable iron delivery for simultaneous management of IBD and its IDA comorbidity. Experimental results demonstrated that PPFeCs alleviated dextran sulfate sodium-induced colonic inflammation, strengthened epithelial barrier integrity through upregulation of tight junction proteins, and ameliorated systemic iron deficiency by restoring hemoglobin levels, thereby confirming their therapeutic potential for treating IBD-IDA comorbidity. Mechanistically, PPFeCs reprogrammed macrophage glucose metabolism by shifting the balance from glycolysis to oxidative phosphorylation through Phosphoinositide 3-kinas/Protein kinase B (PI3K/Akt) pathway modulation. This metabolic switch synergized with Nuclear factor-kappa B (NF-κB) signaling inhibition to drive macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotypes, thereby breaking the vicious cycle of inflammation and oxidative stress. Our findings not only elucidate the multifaceted therapeutic mechanisms of PPFeCs but also lay the groundwork for developing polysaccharide-metal-based nanozymes for treating IBD and its associated complications.
