Neutrophil-inspired photothermo-responsive drug delivery system for targeted treatment of bacterial infection and endotoxins neutralization.

IF 11.3 1区 医学 Q1 Medicine Biomaterials Research Pub Date : 2023-04-15 DOI:10.1186/s40824-023-00372-z
Chengnan Li, Yingying Gan, Zongshao Li, Mengjing Fu, Yuzhen Li, Xinran Peng, Yongqiang Yang, Guo-Bao Tian, Yi Yan Yang, Peiyan Yuan, Xin Ding
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Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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中性粒细胞激发的光热反应药物传递系统用于细菌感染的靶向治疗和内毒素中和。
背景:铜绿假单胞菌是一种高毒力的革兰氏阴性菌,可引起严重的医院感染,并对大多数抗生素产生耐药性。目前迫切需要新的治疗策略来治疗这种细菌感染,并降低内毒素(脂多糖,LPS)引起的毒性。中性粒细胞已被证明能够靶向炎症部位和中性粒细胞膜受体,如toll样受体-4 (TLR4)和CD14,并表现出对LPS的特异性亲和力。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。方法:本研究报道了一种中性粒细胞激发的靶向光热治疗、刺激反应性抗生素释放和内毒素中和的抗菌药物递送系统。将光热试剂吲哚菁绿(ICG)和抗生素利福平(RIF)共负载到聚乳酸-共乙醇酸(PLGA)纳米粒子(NP-ICG/RIF)中,再用中性粒细胞膜包裹,得到抗菌递送系统(NM-NP-ICG/RIF)。体外研究了光热疗法和抗生素治疗的炎症靶向性、协同抑菌活性以及内毒素中和作用。采用铜绿假单胞菌诱导的小鼠皮肤脓肿感染模型,评价纳米颗粒- np - icg /RIF的治疗效果。结果:NP-ICG/RIF经近红外激光照射后,产生的热量触发RIF和ICG的释放,对铜绿假单胞菌具有协同的化学-光热抗菌作用(5 min杀灭效率~ 99.99%)。纳米颗粒(NM-NP-ICG/RIF)包裹中性粒细胞样细胞膜囊泡(NMVs)后,特异性结合感染部位的炎症血管内皮细胞,使纳米颗粒具有感染微环境靶向功能,延长滞留时间。重要的是,这是第一次发现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验证了NM-NP-ICG/RIF的体内治疗效果。结论:中性粒细胞激发的抗菌递送系统(NM-NP-ICG/RIF)通过光热治疗和抗生素治疗的协同作用,能够靶向感染微环境,中和内毒素,根除细菌。这种由fda批准的化合物制成的药物输送系统为对抗难以治疗的细菌感染提供了一种有希望的方法。
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来源期刊
Biomaterials Research
Biomaterials Research Medicine-Medicine (miscellaneous)
CiteScore
10.20
自引率
3.50%
发文量
63
审稿时长
30 days
期刊介绍: Biomaterials Research, the official journal of the Korean Society for Biomaterials, is an open-access interdisciplinary publication that focuses on all aspects of biomaterials research. The journal covers a wide range of topics including novel biomaterials, advanced techniques for biomaterial synthesis and fabrication, and their application in biomedical fields. Specific areas of interest include functional biomaterials, drug and gene delivery systems, tissue engineering, nanomedicine, nano/micro-biotechnology, bio-imaging, regenerative medicine, medical devices, 3D printing, and stem cell research. By exploring these research areas, Biomaterials Research aims to provide valuable insights and promote advancements in the biomaterials field.
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