Stabilizing Macrophage Immune States through Fusion-Enabled Nanoparticle-Based Intracellular Drug Depots for Durable Ulcerative Colitis Therapy
Zilong Zhang, Yanhong Shi, Yan Tang, Jiazhe Zhao, Qinyu Li, Anqi Xu, Bingwen Ding, Li Liang, Di Nie, Dongdong Zhang, Xiaohe Jiang, Zhenxing Pan, Rui Wang, Yu Liu, Miaorong Yu, Yong GanAbstract
Ulcerative colitis (UC) is characterized by persistent colonic inflammation accompanied by the accumulation of pro-inflammatory M1-like macrophages, which sustain cytokine production and impair mucosal repair. Promoting a shift toward a pro-resolving M2-like phenotype is therefore a promising strategy, but current macrophage-modulating approaches are often limited by insufficient intracellular drug persistence and rapid phenotypic reversion after treatment withdrawal. Herein, we report a therapeutic strategy designed to achieve prolonged immunomodulation of macrophages. Specifically, we develop an orally administrable, fusion-enabled nanoparticle (OFEN) to enable improved intracellular availability of immunomodulatory agents in macrophages. By tuning the cholesterol content of milk-derived exosome membranes, OFEN exhibited gastrointestinal stability and fusion-biased cellular entry with reduced endolysosomal sequestration. Following cellular uptake, the poly(lactic-co-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.