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Due to the current lack of antibiotic discovery and development, new strategies to fight MDR bacteria are urgently needed. Efforts to develop new antibiotic adjuvants to increase the effectiveness of existing antibiotics and design delivery systems are essential to address this issue. Here, a bioinspired delivery system equipped with combination therapy and paracellular transport is shown to enhance the efficacy against bacterial infections by improving oral delivery. A screening platform is established using an in vitro\u2010induced high polymyxin\u2010resistant strain to acquire plumbagin, which enhances the efficacy of polymyxin. Functionalized milk extracellular vesicles (FMEVs) coloaded with polymyxin and plumbagin cleared 99% of the bacteria within 4\u00a0h. Mechanistic studies revealed that the drug combination damaged the membrane, disrupted energy metabolism, and accelerated bacterial death. Finally, FMEVs are efficiently transported transcellularly through the citric acid\u2010mediated reversible opening of the tight junctions and showed high efficacy against an MDR <jats:italic>Escherichia coli<\/jats:italic>\u2010associated peritonitis\u2013sepsis model in mice. These findings provide a potential therapeutic strategy to improve the efficacy of combination therapy by enhancing oral delivery using a biomimetic delivery platform.<\/jats:p>","DOI":"10.1002\/advs.202406496","type":"journal-article","created":{"date-parts":[[2024,12,25]],"date-time":"2024-12-25T12:45:21Z","timestamp":1735130721000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A Milk Extracellular Vesicle\u2010Based Nanoplatform Enhances Combination Therapy Against Multidrug\u2010Resistant Bacterial Infections"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2448-5431","authenticated-orcid":false,"given":"Shaoqi","family":"Qu","sequence":"first","affiliation":[{"name":"Animal\u2010Derived Food Safety Innovation Team College of Veterinary Medicine Anhui Agricultural University  Hefei 230036 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