Dismantling the Necroptotic Engine: An Oral Theranostic Nanosponge for Ulcerative Colitis

ABSTRACT Ulcerative Colitis (UC) treatments often lack target specificity and have significant side effects. A key pathological driver is the excessive necroptosis of intestinal epithelial cells (IECs), which disrupts the gut barrier. To address this, we designed an intelligent oral theranostic nanoplatform, CurN@I, to dismantle the necroptosis‐inflammation axis. CurN@I consists of a barium sulfate (BaSO 4 ) core for computed tomography (CT) imaging, encapsulated within a pH‐responsive silk protein nanosponge. This scaffold is co‐loaded with a necroptosis inhibitor (Necrostatin‐1s, Nec‐1s) and an antioxidant (demethoxycurcumin, DMC). The nanostructure is condensed in the acidic stomach but swells at the neutral pH of the inflamed intestine for localized drug release. Its negative surface charge facilitates durable electrostatic adhesion to the inflamed mucosa. In murine UC models, oral CurN@I significantly outperformed first‐line clinical drugs. Mechanistic analysis showed it inhibits IEC necroptosis, alleviates oxidative stress, promotes barrier regeneration, and reshapes the gut microbiome. This work presents a non‐invasive, targeted oral strategy that integrates diagnosis with multi‐faceted therapy to restore intestinal homeostasis, demonstrating strong potential for clinical translation.