Chimeric exosomes-derived immunomodulator restoring lymph nodes microenvironment for sensitizing TNBC immunotherapy
Abstract Immunotherapy is a breakthrough in the treatment of triple-negative breast cancer (TNBC), although it is only effective in a portion of patients. Our clinical studies find that pathological elevated level of reactive oxygen species (ROS) and lipid homeostasis imbalance are closely associate...
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62543-x |
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| author | Mengchi Sun Yuxia Wu Zhichao Chen Boyan Zhang Xiaoyang Liu Peipei Ouyang Ping Chen Lujun Chen Zhonggui He Tao Han Heran Li Jin Sun Shuang Cai Qiuhua Luo |
| author_facet | Mengchi Sun Yuxia Wu Zhichao Chen Boyan Zhang Xiaoyang Liu Peipei Ouyang Ping Chen Lujun Chen Zhonggui He Tao Han Heran Li Jin Sun Shuang Cai Qiuhua Luo |
| author_sort | Mengchi Sun |
| collection | DOAJ |
| description | Abstract Immunotherapy is a breakthrough in the treatment of triple-negative breast cancer (TNBC), although it is only effective in a portion of patients. Our clinical studies find that pathological elevated level of reactive oxygen species (ROS) and lipid homeostasis imbalance are closely associated with dysfunction of dendritic cells (DCs) in the immunosuppressive lymph nodes (LNs) microenvironment of TNBC patients following immunotherapy, which greatly affect the immunotherapeutic efficacy. Building on this, we introduce a chimeric exosomes-derived immunomodulator involving the polysulfide bond-bridged mesoporous silica as both the ROS scavenger and responsive carrier nucleus, loading with the lipid modulator toyocamycin and being coated with chimeric exosomes comprising DCs-derived exosomes and Salmonella outer membrane vesicles. This multifaceted immunomodulator can significantly enhance LNs’ homing through homologous targeting and chemokine-guided navigation, enabling ROS-responsive drug release, thereby restoring functions of DCs and LNs immuno-microenvironment. As expected, the immunomodulator significantly improves the responsiveness of TNBC to immunotherapy, exerting potent inhibition on both the primary tumor and metastases, while promoting a substantial increase in central memory T cells within LNs for sustained antitumor immunity. Our study provides a potent strategy for translational immunotherapy through optimizing the LNs microenvironment in TNBC. |
| format | Article |
| id | doaj-art-5a477bad104f43fd97f63c9817bca655 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-5a477bad104f43fd97f63c9817bca6552025-08-20T03:46:25ZengNature PortfolioNature Communications2041-17232025-08-0116111610.1038/s41467-025-62543-xChimeric exosomes-derived immunomodulator restoring lymph nodes microenvironment for sensitizing TNBC immunotherapyMengchi Sun0Yuxia Wu1Zhichao Chen2Boyan Zhang3Xiaoyang Liu4Peipei Ouyang5Ping Chen6Lujun Chen7Zhonggui He8Tao Han9Heran Li10Jin Sun11Shuang Cai12Qiuhua Luo13Department of Pharmacy, The First Hospital of China Medical UniversityDepartment of Pharmacy, The First Hospital of China Medical UniversityWuya College of Innovation, Shenyang Pharmaceutical UniversityDepartment of Pharmacy, The First Hospital of China Medical UniversityDepartment of Pharmacy, The First Hospital of China Medical UniversityDepartment of Pharmacy, The First Hospital of China Medical UniversityDepartment of Pharmacy, The First Hospital of China Medical UniversityDepartment of Pharmacy, The First Hospital of China Medical UniversityJoint International Research, Laboratory of Intelligent Drug Delivery Systems, Ministry of EducationDepartment of Medical Oncology, the First Hospital of China Medical UniversitySchool of Pharmacy, China Medical UniversityJoint International Research, Laboratory of Intelligent Drug Delivery Systems, Ministry of EducationDepartment of Pharmacy, The First Hospital of China Medical UniversityDepartment of Pharmacy, The First Hospital of China Medical UniversityAbstract Immunotherapy is a breakthrough in the treatment of triple-negative breast cancer (TNBC), although it is only effective in a portion of patients. Our clinical studies find that pathological elevated level of reactive oxygen species (ROS) and lipid homeostasis imbalance are closely associated with dysfunction of dendritic cells (DCs) in the immunosuppressive lymph nodes (LNs) microenvironment of TNBC patients following immunotherapy, which greatly affect the immunotherapeutic efficacy. Building on this, we introduce a chimeric exosomes-derived immunomodulator involving the polysulfide bond-bridged mesoporous silica as both the ROS scavenger and responsive carrier nucleus, loading with the lipid modulator toyocamycin and being coated with chimeric exosomes comprising DCs-derived exosomes and Salmonella outer membrane vesicles. This multifaceted immunomodulator can significantly enhance LNs’ homing through homologous targeting and chemokine-guided navigation, enabling ROS-responsive drug release, thereby restoring functions of DCs and LNs immuno-microenvironment. As expected, the immunomodulator significantly improves the responsiveness of TNBC to immunotherapy, exerting potent inhibition on both the primary tumor and metastases, while promoting a substantial increase in central memory T cells within LNs for sustained antitumor immunity. Our study provides a potent strategy for translational immunotherapy through optimizing the LNs microenvironment in TNBC.https://doi.org/10.1038/s41467-025-62543-x |
| spellingShingle | Mengchi Sun Yuxia Wu Zhichao Chen Boyan Zhang Xiaoyang Liu Peipei Ouyang Ping Chen Lujun Chen Zhonggui He Tao Han Heran Li Jin Sun Shuang Cai Qiuhua Luo Chimeric exosomes-derived immunomodulator restoring lymph nodes microenvironment for sensitizing TNBC immunotherapy Nature Communications |
| title | Chimeric exosomes-derived immunomodulator restoring lymph nodes microenvironment for sensitizing TNBC immunotherapy |
| title_full | Chimeric exosomes-derived immunomodulator restoring lymph nodes microenvironment for sensitizing TNBC immunotherapy |
| title_fullStr | Chimeric exosomes-derived immunomodulator restoring lymph nodes microenvironment for sensitizing TNBC immunotherapy |
| title_full_unstemmed | Chimeric exosomes-derived immunomodulator restoring lymph nodes microenvironment for sensitizing TNBC immunotherapy |
| title_short | Chimeric exosomes-derived immunomodulator restoring lymph nodes microenvironment for sensitizing TNBC immunotherapy |
| title_sort | chimeric exosomes derived immunomodulator restoring lymph nodes microenvironment for sensitizing tnbc immunotherapy |
| url | https://doi.org/10.1038/s41467-025-62543-x |
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