Laboratory of Functionalized Molecular Solids, Ministry of Education, Anhui Province Key Laboratory of Biomedical Materials and Chemical Measurement, College of Chemistry and Materials Science, Anhui Normal University, Wuhu 241002, P. R. China.
Biomacromolecules. 2024 May 13;25(5):3190-3199. doi: 10.1021/acs.biomac.4c00339. Epub 2024 May 1.
Intracellular bacteria in dormant states can escape the immune response and tolerate high-dose antibiotic treatment, leading to severe infections. To overcome this challenge, cascade-targeted nanoplatforms that can target macrophages and intracellular bacteria, exhibiting synergetic antibiotic/reactive oxygen species (ROS)/nitric oxide (NO)/immunotherapy, were developed. These nanoplatforms were fabricated by encapsulating trehalose (Tr) and vancomycin (Van) into phosphatidylserine (PS)-coated poly[(4-allylcarbamoylphenylboric acid)--(arginine-methacrylamide)--(,'-bisacryloylcystamine)] nanoparticles (PABS), denoted as PTVP. PS on PTVP simulates a signal of "eat me" to macrophages to promote cell uptake (the first-step targeting). After the uptake, the nanoplatform in the acidic phagolysosomes could release Tr, and the exposed phenylboronic acid on the nanoplatform could target bacteria (the second-step targeting). Nanoplatforms can release Van in response to infected intracellular overexpressed glutathione (GSH) and weak acid microenvironment. l-arginine (Arg) on the nanoplatforms could be catalyzed by upregulated inducible nitric oxide synthase (iNOS) in the infected macrophages to generate nitric oxide (NO). ,'-Bisacryloylcystamine (BAC) on nanoplatforms could deplete GSH, allow the generation of ROS in macrophages, and then upregulate proinflammatory activity, leading to the reinforced antibacterial capacity. This nanoplatform possesses macrophage and bacteria-targeting antibiotic delivery, intracellular ROS, and NO generation, and pro-inflammatory activities (immunotherapy) provides a new strategy for eradicating intracellular bacterial infections.
休眠状态的细胞内细菌可以逃避免疫反应并耐受高剂量抗生素治疗，从而导致严重感染。为了克服这一挑战，开发了级联靶向纳米平台，可以靶向巨噬细胞和细胞内细菌，表现出协同抗生素/活性氧 (ROS)/一氧化氮 (NO)/免疫疗法。这些纳米平台通过将海藻糖 (Tr) 和万古霉素 (Van) 包封在磷脂酰丝氨酸 (PS) 包覆的聚 [(4-丙烯酰胺基苯硼酸)-（精氨酸-甲基丙烯酰胺）-（,'-二丙烯酰基半胱氨酸）] 纳米粒子 (PABS) 中制成，记为 PTVP。PTVP 上的 PS 模拟了巨噬细胞摄取的“吃我”信号，以促进细胞摄取（第一步靶向）。摄取后，纳米平台在酸性吞噬体溶酶体中可以释放 Tr，暴露在纳米平台上的苯硼酸可以靶向细菌（第二步靶向）。纳米平台可以响应感染细胞中过表达的谷胱甘肽 (GSH) 和弱酸性微环境释放 Van。纳米平台上的 l-精氨酸 (Arg) 可以被感染巨噬细胞中上调的诱导型一氧化氮合酶 (iNOS) 催化生成一氧化氮 (NO)。纳米平台上的,'-二丙烯酰基半胱氨酸 (BAC) 可以消耗 GSH，允许巨噬细胞中产生 ROS，然后上调促炎活性，从而增强抗菌能力。这种纳米平台具有靶向巨噬细胞和细菌的抗生素输送、细胞内 ROS 和 NO 的产生以及促炎活性（免疫疗法），为消除细胞内细菌感染提供了新策略。
