Milk-derived extracellular vesicles functionalized with anti-tumour necrosis factor-α nanobody and anti-microbial peptide alleviate ulcerative colitis in mice

IF 15.5 1区 医学 Q1 CELL BIOLOGY Journal of Extracellular Vesicles Pub Date : 2024-06-05 DOI:10.1002/jev2.12462
Renwei Jing, Leijie Zhang, Ruibin Li, Zhongqiu Yang, Jun Song, Qian Wang, Nan Cao, Gang Han, HaiFang Yin
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Abstract

Ulcerative colitis (UC) manifests clinically with chronic intestinal inflammation and microflora dysbiosis. Although biologics can effectively control inflammation, efficient delivery to the colon and colon epithelial cells remains challenging. Milk-derived extracellular vesicles (EV) show promise as an oral delivery tool, however, the ability to load biologics into EV presents challenges to therapeutic applications. Here, we demonstrate that fusing cell-penetrating peptide (TAT) to green fluorescent protein (GFP) enabled biologics loading into EV and protected against degradation in the gastrointestinal environment in vitro and in vivo after oral delivery. Oral administration of EV loaded with anti-tumour necrosis factor-α (TNF-α) nanobody (VHHm3F) (EVVHH) via TAT significantly reduced tissue TNF-α levels and alleviated pathologies in mice with acute UC, compared to VHH alone. In mice with chronic UC, simultaneously introducing VHH and an antimicrobial peptide LL37 into EV (EVLV), then administering orally improved intestinal barrier, inflammation and microbiota balance, resulted in relief of UC-induced depression and anxiety. Collectively, we demonstrated that oral delivery of EVLV effectively alleviated UC in mice and TAT efficiently loaded biologics into EV to confer protection from degradation in the gastrointestinal tract. This therapeutic strategy is promising for UC and is a simple and generalizable approach towards drug-loaded orally-administrable EV treatment for other diseases.

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用抗肿瘤坏死因子-α纳米抗体和抗微生物肽功能化的牛奶衍生细胞外囊泡可缓解小鼠的溃疡性结肠炎。
溃疡性结肠炎(UC)的临床表现为慢性肠道炎症和微生态失调。虽然生物制剂可以有效控制炎症,但要将其高效地输送到结肠和结肠上皮细胞仍具有挑战性。牛奶衍生的细胞外囊泡(EV)有望成为一种口服给药工具,然而,将生物制剂装入EV的能力给治疗应用带来了挑战。在这里,我们证明了将细胞穿透肽(TAT)与绿色荧光蛋白(GFP)融合可将生物制剂装载到EV中,并在体外和体内口服给药后防止其在胃肠道环境中降解。与单独使用VHH相比,通过TAT口服载入抗肿瘤坏死因子-α(TNF-α)纳米抗体(VHHm3F)(EVVHH)的EV能显著降低急性UC小鼠组织中的TNF-α水平,减轻病理变化。在慢性 UC 小鼠中,将 VHH 和抗菌肽 LL37 同时导入 EV(EVLV),然后口服,可改善肠道屏障、炎症和微生物群平衡,缓解 UC 引起的抑郁和焦虑。总之,我们证明了口服 EVLV 能有效缓解小鼠的 UC,而 TAT 能有效地将生物制剂载入 EV,使其免受胃肠道降解的影响。这种治疗策略对治疗多发性硬化症很有希望,而且是一种简单、可推广的方法,可用于其他疾病的药物口服EV治疗。
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来源期刊
Journal of Extracellular Vesicles
Journal of Extracellular Vesicles Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
27.30
自引率
4.40%
发文量
115
审稿时长
12 weeks
期刊介绍: The Journal of Extracellular Vesicles is an open access research publication that focuses on extracellular vesicles, including microvesicles, exosomes, ectosomes, and apoptotic bodies. It serves as the official journal of the International Society for Extracellular Vesicles and aims to facilitate the exchange of data, ideas, and information pertaining to the chemistry, biology, and applications of extracellular vesicles. The journal covers various aspects such as the cellular and molecular mechanisms of extracellular vesicles biogenesis, technological advancements in their isolation, quantification, and characterization, the role and function of extracellular vesicles in biology, stem cell-derived extracellular vesicles and their biology, as well as the application of extracellular vesicles for pharmacological, immunological, or genetic therapies. The Journal of Extracellular Vesicles is widely recognized and indexed by numerous services, including Biological Abstracts, BIOSIS Previews, Chemical Abstracts Service (CAS), Current Contents/Life Sciences, Directory of Open Access Journals (DOAJ), Journal Citation Reports/Science Edition, Google Scholar, ProQuest Natural Science Collection, ProQuest SciTech Collection, SciTech Premium Collection, PubMed Central/PubMed, Science Citation Index Expanded, ScienceOpen, and Scopus.
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