Stabilizing Macrophage Immune States through Fusion-Enabled Nanoparticle-Based Intracellular Drug Depots for Durable Ulcerative Colitis Therapy

Following cellular uptake, the poly(lactic-<i>co</i>-glycolic acid) (PLGA) core served as an intracellular reservoir for the prolonged release of tumor necrosis factor-α (TNF-α) siRNA and curcumin, thereby combining sequence-specific suppression of a central inflammatory mediator with broader immunomodulatory and antioxidative regulation. This intracellular exposure sustained M2-associated phenotypic modulation and reduced pro-inflammatory cytokine production.

In a chronic colitis model, intermittent OFEN administration alleviated disease activity, preserved colonic architecture, and promoted epithelial barrier-associated recovery, producing greater therapeutic benefit than 5-aminosalicylic acid (5-ASA) and the less fusogenic counterpart under the same intermittent dosing schedule. In a dextran sulfate sodium (DSS) rechallenge model, protective effects remained detectable at the day-12 assessment following a single oral administration of OFEN.

Collectively, these findings support fusion-biased, depot-like intracellular retention as a strategy for prolonging macrophage-directed immunomodulation in UC.