Engineered brain‐targeting exosome for reprogramming immunosuppressive microenvironment of glioblastoma
Abstract The immunosuppressive microenvironment of glioblastoma multiforme (GBM) severely impacts the response to various treatments, including systemic chemotherapy. Targeted reprogramming of immunosuppressive GBM microenvironment using RNA interference (RNAi) is largely restricted by poor brain de...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-04-01
|
| Series: | Exploration |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/EXP.20240039 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850179553380532224 |
|---|---|
| author | Jun Yang Yong Li Shaoping Jiang Yuxin Tian Mengjie Zhang Shuai Guo Pengfei Wu Jianan Li Lin Xu Wenpei Li Yushu Wang Huile Gao Yuanyu Huang Yuhua Weng Shaobo Ruan |
| author_facet | Jun Yang Yong Li Shaoping Jiang Yuxin Tian Mengjie Zhang Shuai Guo Pengfei Wu Jianan Li Lin Xu Wenpei Li Yushu Wang Huile Gao Yuanyu Huang Yuhua Weng Shaobo Ruan |
| author_sort | Jun Yang |
| collection | DOAJ |
| description | Abstract The immunosuppressive microenvironment of glioblastoma multiforme (GBM) severely impacts the response to various treatments, including systemic chemotherapy. Targeted reprogramming of immunosuppressive GBM microenvironment using RNA interference (RNAi) is largely restricted by poor brain delivery efficiency and targeting specificity. Herein, an acid‐cleavable transferrin (Tf) decorated engineering exosome‐based brain‐targeting delivery system (ACTE) was proposed to efficiently deliver small interference RNA towards transform growth factor‐β (siTGF‐β) and doxorubicin (DOX) to GBM site for combination chemo‐immunotherapy. The siTGF‐β and DOX co‐loaded ACTE, termed as DOX&siTGF‐β@ACTE (Ds@ACTE), is designed to specifically recognize the Tf receptor (TfR) on the blood‐brain barrier (BBB). Subsequently, Ds@ACTE undergoes acid‐responsive detachment of Tf within lysosome of brain capillary endothelial cells, leading to the separation of DOX&siTGF‐β@Exo (Ds@Exo) from the Tf‐TfR complex and enhanced BBB transcytosis. After crossing BBB, the separated Ds@Exo can further target GBM cells via the homing effect. In vivo studies validated that Ds@ACTE significantly downregulated the TGF‐β expression to reprogram the immunosuppressive microenvironment, and thereby reinforce the chemotherapeutic effect of DOX and DOX‐induced anti‐tumor immune response. The effectiveness of this strategy not only can provide thinking for designing a more intelligent brain‐targeting system based on engineered exosomes but also explore an effective treatment regimen for GBM. |
| format | Article |
| id | doaj-art-6a12a8e9abd64699b9b840d7fc9f4fe1 |
| institution | OA Journals |
| issn | 2766-8509 2766-2098 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Exploration |
| spelling | doaj-art-6a12a8e9abd64699b9b840d7fc9f4fe12025-08-20T02:18:28ZengWileyExploration2766-85092766-20982025-04-0152n/an/a10.1002/EXP.20240039Engineered brain‐targeting exosome for reprogramming immunosuppressive microenvironment of glioblastomaJun Yang0Yong Li1Shaoping Jiang2Yuxin Tian3Mengjie Zhang4Shuai Guo5Pengfei Wu6Jianan Li7Lin Xu8Wenpei Li9Yushu Wang10Huile Gao11Yuanyu Huang12Yuhua Weng13Shaobo Ruan14School of Life Science Advanced Research Institute of Multidisciplinary Science Laboratory of Molecular Medicine and Biotherapy. Beijing Institute of Technology Beijing ChinaSchool of Life Science Advanced Research Institute of Multidisciplinary Science Laboratory of Molecular Medicine and Biotherapy. Beijing Institute of Technology Beijing ChinaSchool of Life Science Advanced Research Institute of Multidisciplinary Science Laboratory of Molecular Medicine and Biotherapy. Beijing Institute of Technology Beijing ChinaSchool of Life Science Advanced Research Institute of Multidisciplinary Science Laboratory of Molecular Medicine and Biotherapy. Beijing Institute of Technology Beijing ChinaSchool of Life Science Advanced Research Institute of Multidisciplinary Science Laboratory of Molecular Medicine and Biotherapy. Beijing Institute of Technology Beijing ChinaSchool of Life Science Advanced Research Institute of Multidisciplinary Science Laboratory of Molecular Medicine and Biotherapy. Beijing Institute of Technology Beijing ChinaSchool of Life Science Advanced Research Institute of Multidisciplinary Science Laboratory of Molecular Medicine and Biotherapy. Beijing Institute of Technology Beijing ChinaSchool of Life Science Advanced Research Institute of Multidisciplinary Science Laboratory of Molecular Medicine and Biotherapy. Beijing Institute of Technology Beijing ChinaSchool of Life Science Advanced Research Institute of Multidisciplinary Science Laboratory of Molecular Medicine and Biotherapy. Beijing Institute of Technology Beijing ChinaSchool of Life Science Advanced Research Institute of Multidisciplinary Science Laboratory of Molecular Medicine and Biotherapy. Beijing Institute of Technology Beijing ChinaDepartment of Biomedical Engineering Tufts University Medford Massachusetts USAWest China School of Pharmacy Sichuan University Chengdu ChinaSchool of Life Science Advanced Research Institute of Multidisciplinary Science Laboratory of Molecular Medicine and Biotherapy. Beijing Institute of Technology Beijing ChinaSchool of Life Science Advanced Research Institute of Multidisciplinary Science Laboratory of Molecular Medicine and Biotherapy. Beijing Institute of Technology Beijing ChinaSchool of Life Science Advanced Research Institute of Multidisciplinary Science Laboratory of Molecular Medicine and Biotherapy. Beijing Institute of Technology Beijing ChinaAbstract The immunosuppressive microenvironment of glioblastoma multiforme (GBM) severely impacts the response to various treatments, including systemic chemotherapy. Targeted reprogramming of immunosuppressive GBM microenvironment using RNA interference (RNAi) is largely restricted by poor brain delivery efficiency and targeting specificity. Herein, an acid‐cleavable transferrin (Tf) decorated engineering exosome‐based brain‐targeting delivery system (ACTE) was proposed to efficiently deliver small interference RNA towards transform growth factor‐β (siTGF‐β) and doxorubicin (DOX) to GBM site for combination chemo‐immunotherapy. The siTGF‐β and DOX co‐loaded ACTE, termed as DOX&siTGF‐β@ACTE (Ds@ACTE), is designed to specifically recognize the Tf receptor (TfR) on the blood‐brain barrier (BBB). Subsequently, Ds@ACTE undergoes acid‐responsive detachment of Tf within lysosome of brain capillary endothelial cells, leading to the separation of DOX&siTGF‐β@Exo (Ds@Exo) from the Tf‐TfR complex and enhanced BBB transcytosis. After crossing BBB, the separated Ds@Exo can further target GBM cells via the homing effect. In vivo studies validated that Ds@ACTE significantly downregulated the TGF‐β expression to reprogram the immunosuppressive microenvironment, and thereby reinforce the chemotherapeutic effect of DOX and DOX‐induced anti‐tumor immune response. The effectiveness of this strategy not only can provide thinking for designing a more intelligent brain‐targeting system based on engineered exosomes but also explore an effective treatment regimen for GBM.https://doi.org/10.1002/EXP.20240039chemo‐resistanceengineered exosomesglioblastomaimmunosuppressive microenvironmentRNA interference |
| spellingShingle | Jun Yang Yong Li Shaoping Jiang Yuxin Tian Mengjie Zhang Shuai Guo Pengfei Wu Jianan Li Lin Xu Wenpei Li Yushu Wang Huile Gao Yuanyu Huang Yuhua Weng Shaobo Ruan Engineered brain‐targeting exosome for reprogramming immunosuppressive microenvironment of glioblastoma Exploration chemo‐resistance engineered exosomes glioblastoma immunosuppressive microenvironment RNA interference |
| title | Engineered brain‐targeting exosome for reprogramming immunosuppressive microenvironment of glioblastoma |
| title_full | Engineered brain‐targeting exosome for reprogramming immunosuppressive microenvironment of glioblastoma |
| title_fullStr | Engineered brain‐targeting exosome for reprogramming immunosuppressive microenvironment of glioblastoma |
| title_full_unstemmed | Engineered brain‐targeting exosome for reprogramming immunosuppressive microenvironment of glioblastoma |
| title_short | Engineered brain‐targeting exosome for reprogramming immunosuppressive microenvironment of glioblastoma |
| title_sort | engineered brain targeting exosome for reprogramming immunosuppressive microenvironment of glioblastoma |
| topic | chemo‐resistance engineered exosomes glioblastoma immunosuppressive microenvironment RNA interference |
| url | https://doi.org/10.1002/EXP.20240039 |
| work_keys_str_mv | AT junyang engineeredbraintargetingexosomeforreprogrammingimmunosuppressivemicroenvironmentofglioblastoma AT yongli engineeredbraintargetingexosomeforreprogrammingimmunosuppressivemicroenvironmentofglioblastoma AT shaopingjiang engineeredbraintargetingexosomeforreprogrammingimmunosuppressivemicroenvironmentofglioblastoma AT yuxintian engineeredbraintargetingexosomeforreprogrammingimmunosuppressivemicroenvironmentofglioblastoma AT mengjiezhang engineeredbraintargetingexosomeforreprogrammingimmunosuppressivemicroenvironmentofglioblastoma AT shuaiguo engineeredbraintargetingexosomeforreprogrammingimmunosuppressivemicroenvironmentofglioblastoma AT pengfeiwu engineeredbraintargetingexosomeforreprogrammingimmunosuppressivemicroenvironmentofglioblastoma AT jiananli engineeredbraintargetingexosomeforreprogrammingimmunosuppressivemicroenvironmentofglioblastoma AT linxu engineeredbraintargetingexosomeforreprogrammingimmunosuppressivemicroenvironmentofglioblastoma AT wenpeili engineeredbraintargetingexosomeforreprogrammingimmunosuppressivemicroenvironmentofglioblastoma AT yushuwang engineeredbraintargetingexosomeforreprogrammingimmunosuppressivemicroenvironmentofglioblastoma AT huilegao engineeredbraintargetingexosomeforreprogrammingimmunosuppressivemicroenvironmentofglioblastoma AT yuanyuhuang engineeredbraintargetingexosomeforreprogrammingimmunosuppressivemicroenvironmentofglioblastoma AT yuhuaweng engineeredbraintargetingexosomeforreprogrammingimmunosuppressivemicroenvironmentofglioblastoma AT shaoboruan engineeredbraintargetingexosomeforreprogrammingimmunosuppressivemicroenvironmentofglioblastoma |