Li Chengnan, Gan Yingying, Li Zongshao, Fu Mengjing, Li Yuzhen, Peng Xinran, Yang Yongqiang, Tian Guo-Bao, Yang Yi Yan, Yuan Peiyan, Ding Xin
School of Pharmaceutical Science (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, 518107, PR China.
Center for Pathogen Research, West China Hospital, Sichuan University, Chengdu, 610041, China.
Biomater Res. 2023 Apr 15;27(1):30. doi: 10.1186/s40824-023-00372-z.
P. aeruginosa, a highly virulent Gram-negative bacterium, can cause severe nosocomial infections, and it has developed resistance against most antibiotics. New therapeutic strategies are urgently needed to treat such bacterial infection and reduce its toxicity caused by endotoxin (lipopolysaccharide, LPS). Neutrophils have been proven to be able to target inflammation site and neutrophil membrane receptors such as Toll-like receptor-4 (TLR4) and CD14, and exhibit specific affinity to LPS. However, antibacterial delivery system based on the unique properties of neutrophils has not been reported.
A neutrophil-inspired antibacterial delivery system for targeted photothermal treatment, stimuli-responsive antibiotic release and endotoxin neutralization is reported in this study. Specifically, the photothermal reagent indocyanine green (ICG) and antibiotic rifampicin (RIF) are co-loaded into poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP-ICG/RIF), followed by coating with neutrophil membrane to obtain antibacterial delivery system (NM-NP-ICG/RIF). The inflammation targeting properties, synergistic antibacterial activity of photothermal therapy and antibiotic treatment, and endotoxin neutralization have been studied in vitro. A P. aeruginosa-induced murine skin abscess infection model has been used to evaluate the therapeutic efficacy of the NM-NP-ICG/RIF.
Once irradiated by near-infrared lasers, the heat generated by NP-ICG/RIF triggers the release of RIF and ICG, resulting in a synergistic chemo-photothermal antibacterial effect against P. aeruginosa (~ 99.99% killing efficiency in 5 min). After coating with neutrophil-like cell membrane vesicles (NMVs), the nanoparticles (NM-NP-ICG/RIF) specifically bind to inflammatory vascular endothelial cells in infectious site, endowing the nanoparticles with an infection microenvironment targeting function to enhance retention time. Importantly, it is discovered for the first time that NMVs-coated nanoparticles are able to neutralize endotoxins. The P. aeruginosa murine skin abscess infection model further demonstrates the in vivo therapeutic efficacy of NM-NP-ICG/RIF.
The neutrophil-inspired antibacterial delivery system (NM-NP-ICG/RIF) is capable of targeting infection microenvironment, neutralizing endotoxin, and eradicating bacteria through a synergistic effect of photothermal therapy and antibiotic treatment. This drug delivery system made from FDA-approved compounds provides a promising approach to fighting against hard-to-treat bacterial infections.
铜绿假单胞菌是一种高毒力革兰氏阴性菌，可引起严重的医院感染，并且已对大多数抗生素产生耐药性。迫切需要新的治疗策略来治疗此类细菌感染并降低其由内毒素（脂多糖，LPS）引起的毒性。已证实中性粒细胞能够靶向炎症部位以及中性粒细胞膜受体，如Toll样受体4（TLR4）和CD14，并对LPS表现出特异性亲和力。然而，基于中性粒细胞独特性质的抗菌递送系统尚未见报道。
本研究报道了一种用于靶向光热治疗、刺激响应性抗生素释放和内毒素中和的受中性粒细胞启发的抗菌递送系统。具体而言，将光热试剂吲哚菁绿（ICG）和抗生素利福平（RIF）共载入聚乳酸-乙醇酸共聚物（PLGA）纳米颗粒（NP-ICG/RIF），随后用中性粒细胞膜包被以获得抗菌递送系统（NM-NP-ICG/RIF）。在体外研究了其炎症靶向特性、光热疗法与抗生素治疗的协同抗菌活性以及内毒素中和作用。利用铜绿假单胞菌诱导的小鼠皮肤脓肿感染模型评估了NM-NP-ICG/RIF的治疗效果。
一旦受到近红外激光照射，NP-ICG/RIF产生的热量会触发RIF和ICG的释放，从而对铜绿假单胞菌产生协同化学-光热抗菌作用（5分钟内杀灭效率约为99.99%）。在用类中性粒细胞膜囊泡（NMVs）包被后，纳米颗粒（NM-NP-ICG/RIF）特异性结合感染部位的炎症血管内皮细胞，赋予纳米颗粒感染微环境靶向功能以延长滞留时间。重要的是，首次发现用NMVs包被的纳米颗粒能够中和内毒素。铜绿假单胞菌小鼠皮肤脓肿感染模型进一步证明了NM-NP-ICG/RIF的体内治疗效果。
受中性粒细胞启发的抗菌递送系统（NM-NP-ICG/RIF）能够靶向感染微环境、中和内毒素，并通过光热疗法和抗生素治疗的协同作用根除细菌。这种由FDA批准的化合物制成的药物递送系统为对抗难治性细菌感染提供了一种有前景的方法。
