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To achieve precise and efficient delivery, in this study, a targeted delivery system embedded probiotics to the colonic inflammatory site CD44 was constructed by covalently linking hyaluronic acid (HA) to cysteine-modified chitosan (CCH) using microfluidic technology. Two probiotic strains, Bifidobacterium bifidum FL-276.1 and Clostridium butyricum ATCC 19398, were encapsulated within the modified chitosan matrix to form probiotics@CCH microspheres (MSs), with an average diameter of approximately 276 \u03bcm. Based on the receptor\u2013ligand binding mechanism of HA and CD44, combined with the intestinal mucosal adhesion properties conferred by cysteine-modified chitosan, the probiotics@CCH MSs exhibited a high capture rate for inflammatory Caco-2 cells and demonstrated prolonged retention and targeted localization in a DSS-induced colitis mouse model. Furthermore, probiotics@CCH MSs contributed to maintaining intestinal homeostasis by modulating gut microbiota composition, enhancing short-chain fatty acid production, and supporting the intestinal barrier integrity. The microfluidic-based delivery system facilitates the precise localization of probiotics within the intestine, providing a theoretical basis for enhancing probiotic applications in gut health management.<\/jats:p>","DOI":"10.1021\/acsami.5c10456","type":"journal-article","created":{"date-parts":[[2025,7,12]],"date-time":"2025-07-12T19:51:29Z","timestamp":1752349889000},"page":"41852-41867","source":"Crossref","is-referenced-by-count":20,"title":["Microfluidic Fabrication\nof Hyaluronic Acid\u2013Cysteine-Modified\nChitosan Microspheres for CD44-Targeted Probiotic Delivery in Colitis\nTreatment"],"prefix":"10.1021","volume":"17","author":[{"given":"Fengzhi","family":"Qiao","sequence":"first","affiliation":[{"name":"Ocean University of China , , ,","place":["Qingdao, China, 266003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya","family":"Luo","sequence":"additional","affiliation":[{"name":"Ocean University of China , , ,","place":["Qingdao, China, 266003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Lei","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital , , , ,","place":["Boston, Massachusetts, United States, 02114"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0538-167X","authenticated-orcid":true,"given":"Shaolei","family":"Wang","sequence":"additional","affiliation":[{"name":"Ocean University of China , , ,","place":["Qingdao, China, 266003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Duan","sequence":"additional","affiliation":[{"name":"Qingdao Vland Biotech Group Co., Ltd. , ,","place":["Qingdao, China, 266006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongchang","family":"Cui","sequence":"additional","affiliation":[{"name":"Qingdao Vland Biotech Group Co., Ltd. , ,","place":["Qingdao, China, 266006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongjie","family":"Liu","sequence":"additional","affiliation":[{"name":"Ocean University of China , , ,","place":["Qingdao, China, 266003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8968-4263","authenticated-orcid":true,"given":"Huaxi","family":"Yi","sequence":"additional","affiliation":[{"name":"Ocean University of China , , ,","place":["Qingdao, China, 266003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristabelle","family":"De Souza","sequence":"additional","affiliation":[{"name":"Stanford University , , , ,","place":["Stanford, California, United States, 94305"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3613-4997","authenticated-orcid":true,"given":"Guanhua","family":"Xuan","sequence":"additional","affiliation":[{"name":"Ocean University of China , , ,","place":["Qingdao, China, 266003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6315-1338","authenticated-orcid":true,"given":"Xiangzhao","family":"Mao","sequence":"additional","affiliation":[{"name":"Ocean University of China , , ,","place":["Qingdao, China, 266003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8000-5324","authenticated-orcid":true,"given":"Zhao","family":"Ma","sequence":"additional","affiliation":[{"name":"Shandong University , , ,","place":["Jinan, Shandong, China, 250012"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3459-2975","authenticated-orcid":true,"given":"Lanwei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Ocean University of China , , ,","place":["Qingdao, China, 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Agric.\nFood Chem."},{"issue":"24","key":"2026072521074349300_cit42","doi-asserted-by":"publisher","first-page":"13593","DOI":"10.1021\/acs.jafc.4c00365","article-title":"Bifidobacterium bifidum ameliorates dss-induced\ncolitis in mice by regulating microbial metabolome and targeting gut\nmicrobiota","volume":"72","author":"Han","year":"2024","journal-title":"J. Agric. Food Chem."},{"issue":"48","key":"2026072521074349300_cit43","doi-asserted-by":"publisher","first-page":"13282","DOI":"10.1021\/acs.jafc.9b05744","article-title":"Orally administered\nCLA Ameliorates DSS-Induced Colitis in Mice via Intestinal Barrier\nImprovement, Oxidative Stress Reduction, and Inflammatory Cytokine\nand Gut Microbiota Modulation","volume":"67","author":"Chen","year":"2019","journal-title":"J. Agric. 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