{"title":"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。","authors":"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","doi":"10.1186/s13036-025-00538-4","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":15053,"journal":{"name":"Journal of Biological Engineering","volume":"19 1","pages":"65"},"PeriodicalIF":6.5000,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273004/pdf/","citationCount":"0","resultStr":"{\"title\":\"Lactic acid bacteria as microbial cell factories for the in vivo delivery of therapeutic proteins as secretable TAT fusion products.\",\"authors\":\"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\",\"doi\":\"10.1186/s13036-025-00538-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":15053,\"journal\":{\"name\":\"Journal of Biological Engineering\",\"volume\":\"19 1\",\"pages\":\"65\"},\"PeriodicalIF\":6.5000,\"publicationDate\":\"2025-07-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273004/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Biological Engineering\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1186/s13036-025-00538-4\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMICAL RESEARCH METHODS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Biological Engineering","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s13036-025-00538-4","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMICAL RESEARCH METHODS","Score":null,"Total":0}
Lactic acid bacteria as microbial cell factories for the in vivo delivery of therapeutic proteins as secretable TAT fusion products.
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.
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.