Qu Shaoqi, Yang Shuo, Xu Qingjun, Zhang Mengying, Gao Feng, Wu Yongning, Li Lin
Animal-Derived Food Safety Innovation Team, College of Veterinary Medicine, Anhui Agricultural University, Hefei, 230036, China.
Research Unit of Food Safety, Chinese Academy of Medical Sciences (No. 2019RU014), NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment (CFSA), Beijing, 100022, China.
Adv Sci (Weinh). 2025 Feb;12(7):e2406496. doi: 10.1002/advs.202406496. Epub 2024 Dec 25.
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.
多重耐药（MDR）细菌引起的感染发生率不断上升，推动了对新型抗菌药物的需求。由于目前抗生素发现和开发的匮乏，迫切需要对抗MDR细菌的新策略。开发新型抗生素佐剂以提高现有抗生素的有效性以及设计递送系统对于解决这一问题至关重要。在此，展示了一种具有联合疗法和细胞旁转运功能的仿生递送系统，通过改善口服给药来增强抗细菌感染的疗效。利用体外诱导的高多粘菌素抗性菌株建立了一个筛选平台，以获得能增强多粘菌素疗效的白花丹醌。共装载多粘菌素和白花丹醌的功能化乳细胞外囊泡（FMEV）在4小时内清除了99%的细菌。机制研究表明，药物组合破坏了细胞膜，扰乱了能量代谢，并加速了细菌死亡。最后，FMEV通过柠檬酸介导的紧密连接可逆性开放有效地跨细胞转运，并对小鼠的MDR大肠杆菌相关腹膜炎-败血症模型显示出高疗效。这些发现提供了一种潜在的治疗策略，即通过使用仿生递送平台增强口服给药来提高联合疗法的疗效。
