{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:01:20Z","timestamp":1787029280156,"version":"build-2736575974"},"reference-count":33,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82172560"],"award-info":[{"award-number":["82172560"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82172560"],"award-info":[{"award-number":["82172560"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012620","name":"Taishan Scholar Foundation of Shandong Province, China","doi-asserted-by":"publisher","award":["tsqn202211229"],"award-info":[{"award-number":["tsqn202211229"]}],"id":[{"id":"10.13039\/100012620","id-type":"DOI","asserted-by":"publisher"}]},{"name":"leading talents at the provincial level in Yantai city, China"},{"name":"Yantai Natural Science Foundation Project, China","award":["ZR2025LZ936"],"award-info":[{"award-number":["ZR2025LZ936"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Purpose: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder strongly associated with intestinal microbial dysregulation. Although 5-aminosalicylic acid (5-ASA) is widely used in the clinical management of IBD, its therapeutic efficacy is often limited. To address this, the present study aimed to develop a bifidobacterium-derived extracellular vesicle-based drug delivery system (B-MVs@5-ASA) to enhance the therapeutic outcomes of IBD. Methods: B-MVs were isolated by PEG precipitation and loaded with 5-ASA via sonication to obtain B-MVs@5-ASA. Their morphology, particle size, zeta potential, and encapsulation efficiency were analyzed using TEM, DLS, and UV spectrophotometry. Cellular uptake, cytotoxicity (LDH and NO assays), and anti-inflammatory effects were assessed in RAW 264.7 and Caco-2 cells. A DSS-induced colitis mouse model was established to evaluate therapeutic efficacy. Cytokines (ELISA), colon histopathology (H&amp;E), tight-junction proteins (IF), and gut microbiota composition (16S rRNA sequencing) were systematically analyzed. Results: B-MVs@5-ASA exhibited a particle size of 104.3 \u00b1 2.81 nm and an encapsulation efficiency of 11.14% \u00b1 3.63%. B-MVs@5-ASA exhibited the strongest anti-inflammatory effect in vitro and most effectively alleviated DSS-induced colitis in vivo, outperforming monotherapies in reducing inflammation, tissue damage, and enhancing barrier integrity. B-MVs@5-ASA further promoted goblet cell regeneration and beneficially modulated the gut microbiota by enriching Akkermansia and suppressing Escherichia, thereby restoring microbial homeostasis. Conclusions: B-MVs@5-ASA provides potent anti-inflammatory and mucosal-protective effects by modulating cytokine balance, enhancing epithelial barrier function, and reshaping gut microbiota. These findings highlight probiotic vesicle-based nanoplatforms as a safe and promising strategy for targeted IBD therapy.<\/jats:p>","DOI":"10.3390\/pharmaceutics18050553","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T12:20:25Z","timestamp":1777551625000},"page":"553","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Modulation of Inflammation and Gut Microbiota by a Bifidobacterium longum Extracellular Vesicle-Based Drug Delivery System for Alleviating Inflammatory Bowel Disease"],"prefix":"10.3390","volume":"18","author":[{"given":"Chunlei","family":"Ma","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai 264003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shang","family":"Shi","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai 264003, China"},{"name":"Department of Microbiology, College of Life Sciences, Shandong Agricultural University, Taian 271018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenke","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai 264003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boqing","family":"Li","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai 264003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqin","family":"Li","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai 264003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingzi","family":"Cui","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai 264003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangshu","family":"Li","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai 264003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoying","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai 264003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4452-2359","authenticated-orcid":false,"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai 264003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1053\/j.gastro.2014.02.009","article-title":"The microbiome in inflammatory bowel disease: Current status and the future ahead","volume":"146","author":"Kostic","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1038\/nrgastro.2017.136","article-title":"Environmental triggers in IBD: A review of progress and evidence","volume":"15","author":"Ananthakrishnan","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2068","DOI":"10.3748\/wjg.v30.i15.2068","article-title":"Combination treatment of inflammatory bowel disease: Present status and future perspectives","volume":"30","author":"Triantafillidis","year":"2024","journal-title":"World J. Gastroenterol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1016\/j.tim.2023.05.010","article-title":"Bacterial extracellular vesicles: An emerging avenue to tackle diseases","volume":"31","author":"Xie","year":"2023","journal-title":"Trends Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/s41596-019-0236-5","article-title":"Analyzing bacterial extracellular vesicles in human body fluids by orthogonal biophysical separation and biochemical characterization","volume":"15","author":"Tulkens","year":"2020","journal-title":"Nat. Protoc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"14713","DOI":"10.1021\/acs.jafc.4c01758","article-title":"Lactobacillus plantarum-derived extracellular vesicles modulate macrophage polarization and gut homeostasis for alleviating ulcerative colitis","volume":"72","author":"Chen","year":"2024","journal-title":"J. Agric. Food Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1186\/s12951-024-02979-3","article-title":"Probiotic-derived extracellular vesicles alleviate AFB1-induced intestinal injury by modulating the gut microbiota and AHR activation","volume":"22","author":"Li","year":"2024","journal-title":"J. Nanobiotechnol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.jare.2024.03.011","article-title":"Extracellular vesicles derived from Lactobacillus johnsonii promote gut barrier homeostasis by enhancing M2 macrophage polarization","volume":"69","author":"Tao","year":"2024","journal-title":"J. Adv. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e0136822","DOI":"10.1128\/spectrum.01368-22","article-title":"Clostridium butyricum and its derived extracellular vesicles modulate gut homeostasis and ameliorate acute experimental colitis","volume":"10","author":"Ma","year":"2022","journal-title":"Microbiol. Spectr."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Zhang, L., Ma, S., Liang, H., Chen, X., and Zhao, J. (2024). AKK-derived outer membrane vesicles alleviate indomethacin-induced mucin secretion reduction in LS174T cells by inhibiting endoplasmic reticulum stress. Front. Mol. Biosci., 11.","DOI":"10.3389\/fmolb.2024.1418876"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2949","DOI":"10.2147\/IJN.S304515","article-title":"Extracellular vesicles from Akkermansia muciniphila elicit antitumor immunity against prostate cancer via modulation of CD8+ T cells and macrophages","volume":"16","author":"Luo","year":"2021","journal-title":"Int. J. Nanomed."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s41522-025-00663-4","article-title":"Bifidobacterium longum NSP001-derived extracellular vesicles ameliorate ulcerative colitis by modulating T cell responses in gut microbiota-(in)dependent manners","volume":"11","author":"Nie","year":"2025","journal-title":"npj Biofilms Microbiomes"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8030297","DOI":"10.1155\/2021\/8030297","article-title":"Bifidobacterium longum: Protection against inflammatory bowel disease","volume":"2021","author":"Yao","year":"2021","journal-title":"J. Immunol. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2186098","DOI":"10.1080\/19490976.2023.2186098","article-title":"Efficacy of Bifidobacterium longum alone or in multi-strain probiotic formulations during early life and beyond","volume":"15","author":"Mills","year":"2023","journal-title":"Gut Microbes"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e01464-20","DOI":"10.1128\/AEM.01464-20","article-title":"Extracellular vesicles produced by Bifidobacterium longum export mucin-binding proteins","volume":"86","author":"Nishiyama","year":"2020","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2763","DOI":"10.2217\/nnm-2019-0140","article-title":"Biocompatibility in regenerative nanomedicine","volume":"14","author":"Zor","year":"2019","journal-title":"Nanomedicine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4299","DOI":"10.1016\/j.ijbiomac.2020.09.036","article-title":"Sulfated polysaccharide from Turbinaria ornata suppress lipopolysaccharide-induced inflammatory response in RAW 264.7 macrophages","volume":"164","author":"Bhardwaj","year":"2020","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Cao, Y., Chen, J., Ren, G., Zhang, Y., Tan, X., and Yang, L. (2019). Punicalagin prevents inflammation in LPS-induced RAW264.7 macrophages by inhibiting FoxO3a\/autophagy signaling pathway. Nutrients, 11.","DOI":"10.3390\/nu11112794"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41522-023-00400-9","article-title":"Extracellular vesicles of the Gram-positive gut symbiont Bifidobacterium longum induce immune-modulatory, anti-inflammatory effects","volume":"9","author":"Mandelbaum","year":"2023","journal-title":"npj Biofilms Microbiomes"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.3892\/mmr.2017.6153","article-title":"5-ASA-loaded SiO2 nanoparticles-a novel drug delivery system targeting therapy on ulcerative colitis in mice","volume":"15","author":"Tang","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"106917","DOI":"10.1016\/j.fbio.2025.106917","article-title":"Extracellular vesicles from Lactiplantibacillus plantarum: A novel approach to lowering 5-ASA dosage in ulcerative colitis","volume":"69","author":"Tao","year":"2025","journal-title":"Food Biosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1111\/j.1365-2982.2012.01921.x","article-title":"Intestinal barrier function in health and gastrointestinal disease","volume":"24","author":"Camilleri","year":"2012","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.mucimm.2023.01.006","article-title":"Stromal regulation of the intestinal barrier","volume":"16","author":"Sylvestre","year":"2023","journal-title":"Mucosal Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"155","DOI":"10.3892\/etm.2020.9284","article-title":"Inhibition of miRNA-29a regulates intestinal barrier function in diarrhea-predominant irritable bowel syndrome by upregulating ZO-1 and CLDN1","volume":"20","author":"Zhu","year":"2020","journal-title":"Exp. Ther. Med."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Shi, Y., Guo, S., Zhou, J., Xu, P., and Wang, Y. (2024). Black tea preserves intestinal homeostasis through balancing barriers and microbiota in mice. Front. Nutr., 11.","DOI":"10.3389\/fnut.2024.1367047"},{"key":"ref_26","first-page":"e178525","article-title":"Chlorination of epithelial tight junction proteins by neutrophil myeloperoxidase promotes barrier dysfunction and mucosal inflammation","volume":"9","author":"Cartwright","year":"2024","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Muro, P., Zhang, L., Li, S., Zhao, Z., Jin, T., Mao, F., and Mao, Z. (2024). The emerging role of oxidative stress in inflammatory bowel disease. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1390351"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"11757","DOI":"10.1039\/D4FO04194A","article-title":"Dietary Lactobacillus johnsonii-derived extracellular vesicles ameliorate acute colitis by regulating gut microbiota and maintaining intestinal barrier homeostasis","volume":"15","author":"Li","year":"2024","journal-title":"Food Funct."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e70013","DOI":"10.1002\/mnfr.70013","article-title":"Probiotic Lactobacillus-derived extracellular vesicles: Insights into Disease Prevention and Management","volume":"69","author":"Yadav","year":"2025","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"122107","DOI":"10.1016\/j.biomaterials.2023.122107","article-title":"Engineering fucoxanthin-loaded probiotics\u2019 membrane vesicles for the dietary intervention of colitis","volume":"297","author":"Liang","year":"2023","journal-title":"Biomaterials"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"eaap8914","DOI":"10.1126\/scitranslmed.aap8914","article-title":"Gut microbiota composition and functional changes in inflammatory bowel disease and irritable bowel syndrome","volume":"10","author":"Vila","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"8695","DOI":"10.1007\/s00210-025-03787-8","article-title":"Akkermansia muciniphila relieves inflammatory response in DSS-induced ulcerative colitis in mice through regulating macrophage polarization via SCFAs-SLC52A2\/FFAR2 pathway","volume":"398","author":"Zhang","year":"2025","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"26014","DOI":"10.1021\/acs.jafc.5c04623","article-title":"Probiotics and postbiotics produced by Lacticaseibacillus rhamnosus 1.0320 isolated from traditional fermented dairy products alleviate DSS-induced colitis by modulating the gut microbiota and intestinal metabolism","volume":"73","author":"Zhang","year":"2025","journal-title":"J. Agric. Food Chem."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/5\/553\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T16:13:13Z","timestamp":1779207193000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/5\/553"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,30]]},"references-count":33,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["pharmaceutics18050553"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18050553","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,30]]}}}