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This study presents a microemulsion delivery system that utilizes chitosan\/sodium tripolyphosphate (CS\/STPP) to enhance the stability of kernel\u2010loaded insulin and increase bioavailability via intestinal absorption and lymphatic transport. The insulin\/chitosan\/sodium tripolyphosphate\u2010microemulsion (Ins\/CS\/STPP\u2010ME) is a particle size of (81.03 \u00b1\u00a07.19) nm and a polydispersity index (PDI) of (0.313 \u00b1\u00a00.013).\u00a0Infrared spectroscopy confirms insulin encapsulation. Ins\/CS\/STPP\u2010ME exhibits favorable stability and releasesproperties in gastrointestinal fluids, retaining a maximum of (53.076 \u00b1\u00a012.587)% insulin in a pepsin environment and (62.982 \u00b1\u00a013.105)% in a trypsin environment after 60 min. In vivo studies have demonstrated that the addition of CS\/STPP to the internal phase of Ins\/CS\/STPP\u2010ME results in a rapid onset of action and sustained hypoglycaemic effect in diabetic rats. Lymphatic blockade by cycloheximide verified Ins\/CS\/STPP\u2010ME and its ability to cross the gut and enter the bloodstream via lymphatic transport. This work demonstrates that Ins\/CS\/STPP\u2010ME can stabilize proteins in the gastrointestinal environment, facilitate lymphatic absorption, enhance bioavailability, and provide longer\u2010lasting hypoglycemic effects, thus providing the possibility for oral biomacromolecule delivery.<\/jats:p>","DOI":"10.1002\/mabi.202400520","type":"journal-article","created":{"date-parts":[[2025,3,2]],"date-time":"2025-03-02T10:46:05Z","timestamp":1740912365000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Chitosan\/Sodium Tripolyphosphate Microemulsion Enhanced Oral Insulin Delivery via Intestinal Lymphoid"],"prefix":"10.1002","volume":"25","author":[{"given":"Zhengpeng","family":"Zhong","sequence":"first","affiliation":[{"name":"School of Pharmacy and Bioengineering Chongqing University of Technology  69 Hongguang Avenue Chongqing 400054 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7001-2639","authenticated-orcid":false,"given":"Fuping","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Bioengineering Chongqing University of Technology  69 Hongguang Avenue Chongqing 400054 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Gong","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Bioengineering Chongqing University of Technology  69 Hongguang Avenue Chongqing 400054 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changfu","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Bioengineering Chongqing University of Technology  69 Hongguang Avenue Chongqing 400054 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guobao","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Bioengineering Chongqing University of Technology  69 Hongguang Avenue Chongqing 400054 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongmin","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Bioengineering Chongqing University of Technology  69 Hongguang Avenue Chongqing 400054 China"},{"name":"The Center Affiliated Hospital of Chongqing University of Technology  Intersection of Lishi Road and Mawangping Main Street, Banan District Chongqing 400054 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,27]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2024.1447148"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/hsr2.2004"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e35636"},{"key":"e_1_2_9_4_1","first-page":"25","author":"Andreadi A.","year":"2024","journal-title":"Int. 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