Melittin‐Loaded Multifunctional Nanozyme for Ulcerative Colitis Treatment via Enzyme‐Immunotherapy and Ferroptosis Inhibition

Abstract In ulcerative colitis (UC), oxidative stress (OS) and iron overload disrupt immune homeostasis and intestinal barrier function, exacerbating inflammation through effects on macrophages and intestinal epithelial cells (IECs). Reversing macrophage‐driven inflammation and restoring homeostasis of IECs are effective strategies for treating UC. In this study, a multifunctional nanozyme (PDA‐Rh@Mel) is reported consisting of polydopamine nanoparticles (PDA) as the core, in situ‐grown rhodium (Rh) aggregates, and loaded melittin (Mel). PDA‐Rh@Mel efficiently aggregates at the site of inflammation through electrostatic interactions, exhibits cascading enzyme catalytic activity to reduce OS, and performs macrophage reprogramming. By chelating iron ions, scavenging reactive oxygen and nitrogen species, and protecting mitochondria, PDA‐Rh@Mel maintains homeostasis of IECs, preventing further barrier damage and exacerbation of UC. Network pharmacological and histological evaluations show that PDA‐Rh@Mel alleviated symptoms by inhibiting the IL‐17 signaling pathway. These findings demonstrate that PDA‐Rh@Mel can maintain redox balance, iron homeostasis, and immune equilibrium, representing a highly promising therapeutic strategy for UC.