Huang Diandian, Kang Xiaoxu, Yin Zibo, Zhao Dongdong, Ning Yuchen, Liu Huan, Li Feng, Xie Wensheng, Li Guofeng, Wang Xing
State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, PR China.
Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing 100029, PR China.
ACS Nano. 2025 Jul 22;19(28):26075-26090. doi: 10.1021/acsnano.5c06864. Epub 2025 Jul 11.
Intracellular bacteria that survive high-dose antibiotic treatment are recognized as persisters, serving as reservoirs for recurrent infections. While enhancing bacterial metabolism has restored antibiotic efficacy against planktonic persisters, it is ineffective against intracellular forms due to host-imposed nutrient deprivation. To address this, we developed FAlsBm@Rif, a poly(amino acid)-based nanodrug designed to sensitize intracellular persisters to antibiotics via on-site serine delivery. FAlsBm@Rif is constructed by encapsulating rifampicin in serine- and mannose-functionalized copolymers, FAlsBm. Upon uptake of FAlsBm@Rif by macrophages through mannose-mediated endocytosis, the mannose ligand dissociates within the host cell, exposing phenylboronic acid groups to the nanodrug. This enables FAlsBm@Rif to specifically target the peptidoglycan of intracellular persisters. In this way, FAlsBm@Rif employs a cascade-targeting mechanism to precisely navigate both host cells and intracellular persisters, ensuring the localized release of serine and rifampicin at bacterial loci, thus counteracting host-imposed nutrient deprivation. On-site serine delivery shifts persisters to a fermentation pathway under host-induced stress, boosting ATP production and membrane potential. This metabolic shift reverses persistence by alleviating the stringent response and reducing cell wall stress. Consequently, FAlsBm@Rif eradicated 99.78% of intracellular persisters in vivo, significantly outperforming Rif alone (63.41%). This strategy offers a promising approach to combating intracellular persisters.
在高剂量抗生素治疗下存活的细胞内细菌被认为是持留菌，是反复感染的储存库。虽然增强细菌代谢已恢复了抗生素对浮游持留菌的疗效，但由于宿主造成的营养剥夺，对细胞内形式的持留菌无效。为了解决这个问题，我们开发了FAlsBm@Rif，一种基于聚氨基酸的纳米药物，旨在通过现场递送丝氨酸使细胞内持留菌对抗生素敏感。FAlsBm@Rif是通过将利福平封装在丝氨酸和甘露糖功能化的共聚物FAlsBm中构建而成。巨噬细胞通过甘露糖介导的内吞作用摄取FAlsBm@Rif后，甘露糖配体在宿主细胞内解离，使纳米药物暴露苯硼酸基团。这使得FAlsBm@Rif能够特异性靶向细胞内持留菌的肽聚糖。通过这种方式，FAlsBm@Rif采用级联靶向机制精确地定位宿主细胞和细胞内持留菌，确保丝氨酸和利福平在细菌位点局部释放，从而抵消宿主造成的营养剥夺。现场递送丝氨酸使持留菌在宿主诱导的应激下转变为发酵途径，提高ATP生成和膜电位。这种代谢转变通过减轻严格反应和降低细胞壁应激来逆转持留状态。因此，FAlsBm@Rif在体内根除了99.78%的细胞内持留菌，显著优于单独使用利福平（63.41%）。该策略为对抗细胞内持留菌提供了一种有前景的方法。
