The increasing occurrence of infections caused by multidrug-resistant (MDR) bacteria drives the need for new antibacterial drugs. 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-induced high polymyxin-resistant 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 h. 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-mediated reversible opening of the tight junctions and showed high efficacy against an MDR Escherichia coli-associated peritonitis-sepsis 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.