2026-10-10T16:15:20Z https://api.figshare.com/v2/oai

oai:figshare.com:article/34001273 2026-09-25T20:05:57Z category_4 category_7 category_13 category_19 category_21 category_873 category_106 category_46 category_931 category_64 category_132 portal_63 item_type_2 month_year_09_2026

Stabilizing Macrophage Immune States through Fusion-Enabled Nanoparticle-Based Intracellular Drug Depots for Durable Ulcerative Colitis Therapy Zilong Zhang (535429) Yanhong Shi (141141) Yan Tang (195081) Jiazhe Zhao (25112111) Qinyu Li (3493451) Anqi Xu (11788691) Bingwen Ding (18504141) Li Liang (365079) Di Nie (7821557) Dongdong Zhang (644246) Xiaohe Jiang (18562458) Zhenxing Pan (1556332) Rui Wang (52434) Yu Liu (6938) Miaorong Yu (3200046) Yong Gan (803762) Biochemistry Medicine Genetics Pharmacology Biotechnology Chemical Sciences not elsewhere classified Science Policy Immunology Information Systems not elsewhere classified Cancer Infectious Diseases tumor necrosis factor thereby combining sequence sustain cytokine production single oral administration rapid phenotypic reversion promoted epithelial barrier preserved colonic architecture less fusogenic counterpart intermittent dosing schedule impair mucosal repair following cellular uptake dextran sulfate sodium derived exosome membranes 12 assessment following inflammatory cytokine production central inflammatory mediator reduced endolysosomal sequestration chronic colitis model associated phenotypic modulation >- glycolic acid therapeutic strategy designed biased cellular entry achieve prolonged immunomodulation like intracellular retention findings support fusion inflammatory m1 rechallenge model prolonged release intracellular reservoir directed immunomodulation associated recovery aminosalicylic acid like phenotype treatment withdrawal specific suppression shift toward resolving m2 promising strategy prolonging macrophage orally administrable often limited modulating approaches lactic -< immunomodulatory agents enabled nanoparticle current macrophage core served co </ cholesterol content 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-<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. 2026-09-25T00:00:00Z Dataset Media 10.1021/acsnano.6c03677.s002 https://figshare.com/articles/media/Stabilizing_Macrophage_Immune_States_through_Fusion-Enabled_Nanoparticle-Based_Intracellular_Drug_Depots_for_Durable_Ulcerative_Colitis_Therapy/34001273 CC BY-NC 4.0