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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-\u03b1 (TNF-\u03b1) 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.<\/jats:p>","DOI":"10.1021\/acsnano.6c03677","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T21:02:30Z","timestamp":1790370150000},"page":"27019-27040","source":"Crossref","is-referenced-by-count":0,"title":["Stabilizing Macrophage\nImmune States through Fusion-Enabled\nNanoparticle-Based Intracellular Drug Depots for Durable Ulcerative\nColitis Therapy"],"prefix":"10.1021","volume":"20","author":[{"given":"Zilong","family":"Zhang","sequence":"first","affiliation":[{"name":"Shanghai University of Traditional Chinese Medicine , , ,","place":["Shanghai, China, 201203"]},{"name":"Chinese Academy of Sciences , , ,","place":["Shanghai, China, 201203"]},{"name":"Shaanxi University of Chinese Medicine , , ,","place":["Xianyang, China, 712046"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhong","family":"Shi","sequence":"additional","affiliation":[{"name":"Shanghai University of Traditional Chinese Medicine , , ,","place":["Shanghai, China, 201203"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Tang","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Shanghai, China, 201203"]},{"name":"Nanjing University of Chinese Medicine , , ,","place":["Nanjing, China, 210023"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiazhe","family":"Zhao","sequence":"additional","affiliation":[{"name":"Shenyang Pharmaceutical University , , ,","place":["Shenyang, China, 110016"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinyu","family":"Li","sequence":"additional","affiliation":[{"name":"Nanjing University of Chinese Medicine , , ,","place":["Nanjing, China, 210023"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anqi","family":"Xu","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Shanghai, China, 201203"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingwen","family":"Ding","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Shanghai, China, 201203"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Liang","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Shanghai, China, 201203"]},{"name":"Nanjing University of Chinese Medicine , , ,","place":["Nanjing, China, 210023"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Nie","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Shanghai, China, 201203"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongdong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shaanxi University of Chinese Medicine , , ,","place":["Xianyang, China, 712046"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohe","family":"Jiang","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Shanghai, China, 201203"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenxing","family":"Pan","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Shanghai, China, 201203"]},{"name":"Shenyang Pharmaceutical University , , ,","place":["Shenyang, China, 110016"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Wang","sequence":"additional","affiliation":[{"name":"Shanghai University of Traditional Chinese Medicine , , ,","place":["Shanghai, China, 201203"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8526-3122","authenticated-orcid":true,"given":"Yu","family":"Liu","sequence":"additional","affiliation":[{"name":"Fudan University, Ministry of Education , , ,","place":["Shanghai, China, 201203"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0474-5339","authenticated-orcid":true,"given":"Miaorong","family":"Yu","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Shanghai, China, 201203"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4579-994X","authenticated-orcid":true,"given":"Yong","family":"Gan","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Shanghai, China, 201203"]},{"name":"Nanjing University of Chinese Medicine , , ,","place":["Nanjing, China, 210023"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"issue":"10401","key":"2026101310083990400_cit1","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1016\/S0140-6736(23)00966-2","article-title":"Ulcerative\nColitis","volume":"402","author":"Le 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Med."},{"issue":"5","key":"2026101310083990400_cit5","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1016\/j.immuni.2019.10.011","article-title":"Targeting Immune\nCell Wiring in Ulcerative Colitis","volume":"51","author":"Neurath","year":"2019","journal-title":"Immunity"},{"key":"2026101310083990400_cit6","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1146\/annurev-med-052919-120048","article-title":"New Therapeutics for Ulcerative Colitis","volume":"72","author":"Hirten","year":"2021","journal-title":"Annu. Rev. 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Rev. Gastroenterol.\nHepatol."},{"issue":"10","key":"2026101310083990400_cit11","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1038\/s41551-023-01136-9","article-title":"An Injectable\nSubcutaneous\nColon-specific Immune Niche for the Treatment of Ulcerative Colitis","volume":"8","author":"Au","year":"2024","journal-title":"Nat. Biomed. Eng."},{"issue":"9","key":"2026101310083990400_cit12","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1038\/s41575-019-0172-4","article-title":"Macrophages in Intestinal\nInflammation and Resolution: a Potential Therapeutic Target in IBD","volume":"16","author":"Na","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"2026101310083990400_cit13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1615340","article-title":"Mechanisms\nand Therapeutic Strategies\nof Macrophages and Neutrophils Inducing Ulcerative Colitis Progression","volume":"16","author":"Wang","year":"2025","journal-title":"Front. Immunol."},{"key":"2026101310083990400_cit14","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2025.123601","article-title":"Reprogram\nto Heal: Macrophage Phenotypes as Living Therapeutics","volume":"371","author":"Ghamangiz","year":"2025","journal-title":"Life Sci."},{"key":"2026101310083990400_cit15","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1016\/j.jconrel.2020.01.047","article-title":"Macrophage-based\nNanotherapeutic\nStrategies in Ulcerative Colitis","volume":"320","author":"Zhang","year":"2020","journal-title":"J. Controlled\nRelease"},{"key":"2026101310083990400_cit16","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2022.108176","article-title":"Macrophage Immunometabolism in Inflammatory\nBowel Diseases: From Pathogenesis to Therapy","volume":"238","author":"Pan","year":"2022","journal-title":"Pharmacol. Ther."},{"issue":"6","key":"2026101310083990400_cit17","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202514413","article-title":"Pathology-Driven\nDesign of a Biomimetic Ferromagnetic Nanomedicine for Dual-Mode Treatment\nof Ulcerative Colitis and Colitis-Associated Colorectal Cancer","volume":"38","author":"Liu","year":"2026","journal-title":"Adv. Mater."},{"key":"2026101310083990400_cit18","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2024.107227","article-title":"The Role of Macrophage Polarization in Ulcerative Colitis\nand its Treatment","volume":"199","author":"Qu","year":"2025","journal-title":"Microb. Pathog."},{"key":"2026101310083990400_cit19","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.105796","article-title":"Dioscin\nAmeliorates Murine Ulcerative\nColitis by Regulating Macrophage Polarization","volume":"172","author":"Wu","year":"2021","journal-title":"Pharmacol. Res."},{"key":"2026101310083990400_cit20","doi-asserted-by":"publisher","DOI":"10.1016\/j.cej.2022.139445","article-title":"Dual-targeting\nCelecoxib Nanoparticles Protect Intestinal Epithelium and Regulate\nMacrophage Polarization for Ulcerative Colitis Treatment","volume":"452","author":"Chen","year":"2023","journal-title":"Chem. Eng. J."},{"key":"2026101310083990400_cit21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cclet.2025.112111","article-title":"Shikonin Ameliorates Ulcerative Colitis by Inhibiting\nNecroptosis via Targeting HSPA8","volume":"37","author":"Wang","year":"2026","journal-title":"Chin. Chem.\nLett."},{"issue":"3","key":"2026101310083990400_cit22","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202508532","article-title":"Biocompatible Nanozyme Shell-Armed\nProbiotic with Inflammation Targeting\nand Scavenging Properties Enables Effective Treatment of Colitis","volume":"38","author":"Liang","year":"2026","journal-title":"Adv. Mater."},{"issue":"19","key":"2026101310083990400_cit23","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202309972","article-title":"A Gas Therapy\nStrategy for Intestinal Flora Regulation and Colitis Treatment by\nNanogel-Based Multistage NO Delivery Microcapsules","volume":"36","author":"Fu","year":"2024","journal-title":"Adv. Mater."},{"issue":"11","key":"2026101310083990400_cit24","doi-asserted-by":"publisher","first-page":"4924","DOI":"10.1016\/j.cclet.2022.03.110","article-title":"Oral Colon-targeted Mucoadhesive\nMicelles with Enzyme-responsive Controlled Release of Curcumin for\nUlcerative Colitis Therapy","volume":"33","author":"Zhang","year":"2022","journal-title":"Chin. Chem. Lett."},{"issue":"14","key":"2026101310083990400_cit25","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202309516","article-title":"Transient Mild Photothermia Improves Therapeutic Performance\nof Oral Nanomedicines with Enhanced Accumulation in the Colitis Mucosa","volume":"36","author":"Ma","year":"2024","journal-title":"Adv. Mater."},{"issue":"9","key":"2026101310083990400_cit26","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1007\/s12272-025-01569-7","article-title":"Curcumin for Inflammatory Bowel Disease\nTherapy: Advances in Mechanisms, Clinical Applications, and Drug Delivery","volume":"48","author":"Zhang","year":"2025","journal-title":"Arch. Pharm. 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Mater."},{"issue":"25","key":"2026101310083990400_cit30","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202307247","article-title":"Mulberry Leaf\nLipid Nanoparticles: a Naturally Targeted CRISPR\/Cas9 Oral Delivery\nPlatform for Alleviation of Colon Diseases","volume":"20","author":"Ma","year":"2024","journal-title":"Small"},{"issue":"24","key":"2026101310083990400_cit31","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.202421680","article-title":"Oral Targeted\nMXenzyme \u2013 Armed Probiotic Regulates Intestinal Redox and Microbiota\nHomeostasis to Synergistically Ameliorate Ulcerative Colitis","volume":"35","author":"Peng","year":"2025","journal-title":"Adv. Funct. Mater."},{"issue":"1","key":"2026101310083990400_cit32","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1038\/s41423-019-0315-0","article-title":"Epigenetic Regulation\nof Macrophages: from Homeostasis Maintenance to Host Defense","volume":"17","author":"Chen","year":"2020","journal-title":"Cell. Mol. Immunol."},{"issue":"12","key":"2026101310083990400_cit33","doi-asserted-by":"publisher","first-page":"5258","DOI":"10.7150\/ijbs.115515","article-title":"Recent Advances of\nTrained immunity in Macrophages","volume":"21","author":"Li","year":"2025","journal-title":"Int. J. Biol.\nSci."},{"issue":"39","key":"2026101310083990400_cit34","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.202526444","article-title":"Biomimetic Exosome-Camouflaged pH-Responsive Dendrimer Nanogels as\na Therapeutic Vaccine Against Pancreatic Cancer Through Reprogramming\nof Multiple Cell Types","volume":"36","author":"Li","year":"2026","journal-title":"Adv. Funct. Mater."},{"issue":"1","key":"2026101310083990400_cit35","doi-asserted-by":"publisher","DOI":"10.1186\/s12951-026-04227-2","article-title":"Garlic-derived Exosome-like\nNanovesicle Core-shell Platform for Sequential Infection Treatment\nand Tissue Repair","volume":"24","author":"Gao","year":"2026","journal-title":"J. Nanobiotechnol."},{"issue":"8","key":"2026101310083990400_cit36","doi-asserted-by":"publisher","first-page":"3643","DOI":"10.1016\/j.apsb.2024.04.010","article-title":"Endoplasmic Reticulum-targeted Delivery of Celastrol\nand PD-L1 siRNA for Reinforcing Immunogenic Cell Death and Potentiating\nCancer Immunotherapy","volume":"14","author":"Wang","year":"2024","journal-title":"Acta Pharm. Sin. B"},{"issue":"10","key":"2026101310083990400_cit37","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.202416791","article-title":"Membrane Fusion\nStrategy Boosts Immune Homeostasis, Mobilizing Macrophages to Eliminate\nBacteria and Accelerate Skin Regeneration in Infected Burn Wound","volume":"35","author":"Wang","year":"2025","journal-title":"Adv. Funct. Mater."},{"issue":"1","key":"2026101310083990400_cit38","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-46533-z","article-title":"An Antifouling\nMembrane-fusogenic Liposome for Effective\nIntracellular Delivery In Vivo","volume":"15","author":"Kong","year":"2024","journal-title":"Nat. Commun."},{"issue":"6","key":"2026101310083990400_cit39","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202410507","article-title":"siAkt2-Loaded Nanoparticles\nReprogramming Macrophages to M2 Phenotype\nfor Effective Bone Defect Repair","volume":"38","author":"Cui","year":"2026","journal-title":"Adv. Mater."},{"issue":"6548","key":"2026101310083990400_cit40","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.1126\/science.abc0269","article-title":"NF-\u03baB\nDynamics\nDetermine the Stimulus Specificity of Epigenomic Reprogramming in\nMacrophages","volume":"372","author":"Cheng","year":"2021","journal-title":"Science"},{"key":"2026101310083990400_cit41","doi-asserted-by":"publisher","DOI":"10.1016\/j.mtbio.2025.101895","article-title":"Curcumin-loaded Polydopamine Nanoparticles-based Antioxidant\nScaffold\nPromote Spinal Cord Repair Though Dural-regulation of Macrophage Polarization","volume":"32","author":"Mao","year":"2025","journal-title":"Mater. 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