Oral delivery of therapeutic proteins by engineered bacterial type zero secretion system
Abstract Genetically engineered commensal bacteria are promising living drugs, however, their therapeutic molecules are frequently confined to their colonization sites. Herein, we report an oral protein delivery technology utilizing an engineered bacterial type zero secretion system (T0SS) via outer...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-02-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57153-6 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850190845829971968 |
|---|---|
| author | Xu Gong Shan Liu Bozhang Xia Yichen Wan Shuyi Zhang Baoyan Zhang Zehao Wang Junge Chen Fei Xiao Xing-Jie Liang Yun Yang |
| author_facet | Xu Gong Shan Liu Bozhang Xia Yichen Wan Shuyi Zhang Baoyan Zhang Zehao Wang Junge Chen Fei Xiao Xing-Jie Liang Yun Yang |
| author_sort | Xu Gong |
| collection | DOAJ |
| description | Abstract Genetically engineered commensal bacteria are promising living drugs, however, their therapeutic molecules are frequently confined to their colonization sites. Herein, we report an oral protein delivery technology utilizing an engineered bacterial type zero secretion system (T0SS) via outer membrane vesicles (OMVs). We find that OMVs produced in situ by Escherichia coli Nissle 1917 (EcN) can penetrate the intact gut epithelial barrier to enter the circulation and that epithelial transcytosis involves pinocytosis and dynamin-dependent pathways. EcN is engineered to endogenously load various enzymes into OMVs, and the secreted enzyme-loaded OMVs are able to stably catalyze diverse detoxification reactions against digestive fluid and even enter the circulation. Using hyperuricemic mice and uricase delivery as a demonstration, we demonstrate that the therapeutic efficacy of our engineered EcN with a modified T0SS outperforms that with a direct protein secretion apparatus. The enzyme-loaded OMVs also effectively detoxify human serum samples, highlighting the potential for the clinical treatment of metabolic disorders. |
| format | Article |
| id | doaj-art-01fbe3f1be4a4bd29ad11a383b4f2e40 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-01fbe3f1be4a4bd29ad11a383b4f2e402025-08-20T02:15:08ZengNature PortfolioNature Communications2041-17232025-02-0116111410.1038/s41467-025-57153-6Oral delivery of therapeutic proteins by engineered bacterial type zero secretion systemXu Gong0Shan Liu1Bozhang Xia2Yichen Wan3Shuyi Zhang4Baoyan Zhang5Zehao Wang6Junge Chen7Fei Xiao8Xing-Jie Liang9Yun Yang10Beijing Advanced Innovation Center for Biomedical Engineering, School of Medical Science and Engineering, Beihang UniversityBeijing Advanced Innovation Center for Biomedical Engineering, School of Medical Science and Engineering, Beihang UniversityChinese Academy of Sciences (CAS) Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and TechnologyBeijing Advanced Innovation Center for Biomedical Engineering, School of Medical Science and Engineering, Beihang UniversitySchool of Pharmaceutical Sciences, Tsinghua UniversityBeijing Advanced Innovation Center for Biomedical Engineering, School of Medical Science and Engineering, Beihang UniversityBeijing Advanced Innovation Center for Biomedical Engineering, School of Medical Science and Engineering, Beihang UniversityBeijing Advanced Innovation Center for Biomedical Engineering, School of Medical Science and Engineering, Beihang UniversityDepartment of Thoracic Surgery, China-Japan Friendship HospitalChinese Academy of Sciences (CAS) Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and TechnologyBeijing Advanced Innovation Center for Biomedical Engineering, School of Medical Science and Engineering, Beihang UniversityAbstract Genetically engineered commensal bacteria are promising living drugs, however, their therapeutic molecules are frequently confined to their colonization sites. Herein, we report an oral protein delivery technology utilizing an engineered bacterial type zero secretion system (T0SS) via outer membrane vesicles (OMVs). We find that OMVs produced in situ by Escherichia coli Nissle 1917 (EcN) can penetrate the intact gut epithelial barrier to enter the circulation and that epithelial transcytosis involves pinocytosis and dynamin-dependent pathways. EcN is engineered to endogenously load various enzymes into OMVs, and the secreted enzyme-loaded OMVs are able to stably catalyze diverse detoxification reactions against digestive fluid and even enter the circulation. Using hyperuricemic mice and uricase delivery as a demonstration, we demonstrate that the therapeutic efficacy of our engineered EcN with a modified T0SS outperforms that with a direct protein secretion apparatus. The enzyme-loaded OMVs also effectively detoxify human serum samples, highlighting the potential for the clinical treatment of metabolic disorders.https://doi.org/10.1038/s41467-025-57153-6 |
| spellingShingle | Xu Gong Shan Liu Bozhang Xia Yichen Wan Shuyi Zhang Baoyan Zhang Zehao Wang Junge Chen Fei Xiao Xing-Jie Liang Yun Yang Oral delivery of therapeutic proteins by engineered bacterial type zero secretion system Nature Communications |
| title | Oral delivery of therapeutic proteins by engineered bacterial type zero secretion system |
| title_full | Oral delivery of therapeutic proteins by engineered bacterial type zero secretion system |
| title_fullStr | Oral delivery of therapeutic proteins by engineered bacterial type zero secretion system |
| title_full_unstemmed | Oral delivery of therapeutic proteins by engineered bacterial type zero secretion system |
| title_short | Oral delivery of therapeutic proteins by engineered bacterial type zero secretion system |
| title_sort | oral delivery of therapeutic proteins by engineered bacterial type zero secretion system |
| url | https://doi.org/10.1038/s41467-025-57153-6 |
| work_keys_str_mv | AT xugong oraldeliveryoftherapeuticproteinsbyengineeredbacterialtypezerosecretionsystem AT shanliu oraldeliveryoftherapeuticproteinsbyengineeredbacterialtypezerosecretionsystem AT bozhangxia oraldeliveryoftherapeuticproteinsbyengineeredbacterialtypezerosecretionsystem AT yichenwan oraldeliveryoftherapeuticproteinsbyengineeredbacterialtypezerosecretionsystem AT shuyizhang oraldeliveryoftherapeuticproteinsbyengineeredbacterialtypezerosecretionsystem AT baoyanzhang oraldeliveryoftherapeuticproteinsbyengineeredbacterialtypezerosecretionsystem AT zehaowang oraldeliveryoftherapeuticproteinsbyengineeredbacterialtypezerosecretionsystem AT jungechen oraldeliveryoftherapeuticproteinsbyengineeredbacterialtypezerosecretionsystem AT feixiao oraldeliveryoftherapeuticproteinsbyengineeredbacterialtypezerosecretionsystem AT xingjieliang oraldeliveryoftherapeuticproteinsbyengineeredbacterialtypezerosecretionsystem AT yunyang oraldeliveryoftherapeuticproteinsbyengineeredbacterialtypezerosecretionsystem |