Lactic acid bacteria as microbial cell factories for the in vivo delivery of therapeutic proteins as secretable TAT fusion products.

IF 6.5 3区 生物学 Q1 BIOCHEMICAL RESEARCH METHODS
Giorgio Medici, Giulia Candini, Nicola Mottolese, Beatrice Uguagliati, Federica Trebbi, Manuela Loi, Angelica Marina Bove, Spase Stojanov, Erika Esposito, Rosalba Vitagliano, Federica D'Amico, Silvia Turroni, Jessica Fiori, Aleš Berlec, Stefania Trazzi, Elisabetta Ciani
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引用次数: 0

Abstract

Protein-based therapeutics have garnered increasing attention across various medical fields for their substantial benefits to human health. Existing strategies for intracellular protein delivery, such as cell-penetrating peptide (CPP)-based approaches, including the transactivator of transcription (TAT) peptide, have shown promising results but also present limitations, particularly due to the need for recombinant protein manufacturing and daily invasive administration. To overcome such hindrances and develop delivery tools that are able to foster the production of the protein directly inside the body of patients, we engineered the lactic acid bacterium, Lactococcus lactis, to express and secrete TATκ-GFP protein. After oral administration of the recombinant L. lactis in mice, we found the presence of the TATκ-GFP protein not only in the intestinal wall but also in the mouse liver, heart, and brain. This provides the first evidence that a recombinant TATκ-fused protein, secreted by L. lactis in the mouse host gut, by virtue of the presence of the TATκ peptide, can efficiently pass from the intestinal wall to other organs. With future research and development, this technology based on lactic acid bacteria (LAB) as a platform for the production and delivery of therapeutic proteins could offer significant advancements in the field of therapeutic protein delivery.

乳酸菌作为微生物细胞工厂,作为可分泌的TAT融合产物在体内递送治疗性蛋白。
基于蛋白质的治疗方法因其对人体健康的巨大益处而在各个医学领域受到越来越多的关注。现有的细胞内蛋白递送策略,如基于细胞穿透肽(CPP)的方法,包括转录反激活子(TAT)肽,已经显示出有希望的结果,但也存在局限性,特别是由于需要重组蛋白制造和日常侵入性给药。为了克服这些障碍并开发能够直接在患者体内促进蛋白质生产的递送工具,我们设计了乳酸菌乳酸球菌,以表达和分泌TATκ-GFP蛋白。经小鼠口服重组乳酸乳杆菌后,我们发现TATκ-GFP蛋白不仅存在于肠壁,而且存在于小鼠的肝脏、心脏和大脑中。这提供了第一个证据,证明乳杆菌在小鼠宿主肠道中分泌的重组TATκ融合蛋白,凭借TATκ肽的存在,可以有效地从肠壁传递到其他器官。随着未来的研究和发展,这种基于乳酸菌(LAB)作为生产和递送治疗性蛋白的平台的技术将在治疗性蛋白递送领域取得重大进展。
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来源期刊
Journal of Biological Engineering
Journal of Biological Engineering BIOCHEMICAL RESEARCH METHODS-BIOTECHNOLOGY & APPLIED MICROBIOLOGY
CiteScore
7.10
自引率
1.80%
发文量
32
审稿时长
17 weeks
期刊介绍: Biological engineering is an emerging discipline that encompasses engineering theory and practice connected to and derived from the science of biology, just as mechanical engineering and electrical engineering are rooted in physics and chemical engineering in chemistry. Topical areas include, but are not limited to: Synthetic biology and cellular design Biomolecular, cellular and tissue engineering Bioproduction and metabolic engineering Biosensors Ecological and environmental engineering Biological engineering education and the biodesign process As the official journal of the Institute of Biological Engineering, Journal of Biological Engineering provides a home for the continuum from biological information science, molecules and cells, product formation, wastes and remediation, and educational advances in curriculum content and pedagogy at the undergraduate and graduate-levels. Manuscripts should explore commonalities with other fields of application by providing some discussion of the broader context of the work and how it connects to other areas within the field.
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