Yin Zibo, Huang Diandian, Zhao Dongdong, You Yizhen, Gu Jiaqi, Xie Wensheng, Moriarty T Fintan, Li Guofeng, Wang Xing
State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing, 100029, P. R. China.
AO Research Institute Davos, 7270 Davos, Switzerland.
ACS Appl Mater Interfaces. 2025 Aug 20;17(33):47412-47425. doi: 10.1021/acsami.5c11777. Epub 2025 Aug 8.
Intracellular persisters are a dormant bacterial subpopulation responsible for chronic and recurrent infections due to their ability to evade antibiotic treatment within host cells. However, effective strategies for eliminating these intracellular pathogens remain limited. Herein, we proposed a versatile poly(amino acid)-based platform, F(AM), for the effective eradication of intracellular persisters via on-site antibiotic delivery. The F(AM) platform exhibited dual-targeting capability toward macrophages and persisters, efficiently penetrating cellular barriers and achieving precise antibiotic delivery at intracellular bacterial niches. Sitafloxacin, rifampicin, and polymyxin B were identified from a panel of 11 antibiotic candidates and individually loaded into the F(AM) platform. The resulting nanoparticles markedly improved intracellular drug accumulation, protected antibiotics from degradation within the adverse intracellular environment, and overcame microenvironment-induced bacterial metabolic shifts. Compared with free antibiotics, the drug-loaded F(AM) nanoparticles notably improved their intracellular bactericidal activity. Collectively, this study highlights F(AM) as a robust and versatile platform for overcoming intracellular barriers and restoring antibiotic efficacy, offering a valuable tool for antipersister strategies and intracellular pharmacokinetic investigations.
细胞内持留菌是一种休眠的细菌亚群，由于其能够在宿主细胞内逃避抗生素治疗，因而导致慢性和复发性感染。然而，消除这些细胞内病原体的有效策略仍然有限。在此，我们提出了一种基于聚氨基酸的通用平台F(AM)，用于通过现场抗生素递送有效根除细胞内持留菌。F(AM)平台对巨噬细胞和持留菌具有双靶向能力，能有效穿透细胞屏障，并在细胞内细菌龛位实现精确的抗生素递送。从11种抗生素候选物中筛选出西他沙星、利福平和多粘菌素B，并分别负载到F(AM)平台中。所得纳米颗粒显著提高了细胞内药物积累，保护抗生素在不利的细胞内环境中不被降解，并克服了微环境诱导的细菌代谢转变。与游离抗生素相比载药F(AM)纳米颗粒显著提高了其细胞内杀菌活性。总的来说，本研究突出了F(AM)作为一个强大且通用的平台，可用于克服细胞内屏障和恢复抗生素疗效，为抗持留菌策略和细胞内药代动力学研究提供了一个有价值的工具。
