Exosomal encapsulation of a steviol derivative SD9 to overcome TRAIL resistance as a highly effective therapy against lung cancer
Abstract Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising pro-apoptotic factor. However, it has showed very limited efficacies due to low bioavailability and common drug resistance in cancers. Extracellular vesicle delivery of TRAIL (EV-T) has significantly improv...
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| Format: | Article |
| Language: | English |
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BMC
2025-06-01
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| Series: | Cancer Nanotechnology |
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| Online Access: | https://doi.org/10.1186/s12645-025-00329-y |
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| author | Quanjiang Li Yufeng Xie Wanting Zhang Jun Peng Zhujie Deng Rui Tian Xiubin Kuang Bin Xie Chen Huang Yu Zhao Zhengqiang Yuan |
| author_facet | Quanjiang Li Yufeng Xie Wanting Zhang Jun Peng Zhujie Deng Rui Tian Xiubin Kuang Bin Xie Chen Huang Yu Zhao Zhengqiang Yuan |
| author_sort | Quanjiang Li |
| collection | DOAJ |
| description | Abstract Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising pro-apoptotic factor. However, it has showed very limited efficacies due to low bioavailability and common drug resistance in cancers. Extracellular vesicle delivery of TRAIL (EV-T) has significantly improved the activity and the combination of EV-T with some intrinsic apoptosis-inducing chemical compounds showed further strikingly augmented apoptosis induction in cancers. Previously we synthesized a steviol derivative 9# (SD9) that induced intrinsic apoptosis in cancer cells. However, it has never been examined if SD9 collaborates with EV-T to trigger synergistic apoptosis-induction in cancer cells. Herein, we propose that SD9 may be loaded into EV-T to sensitize TRAIL response for a synergistic anti-cancer therapy. First, TRAIL-transduced mesenchymal stem cells (MSCs) were used to produce EV-Ts. Then SD9 was encapsulated into EV-Ts to prepare the complexed nanodrug SD9@EV-T. The encapsulation of SD9 resulted in not only increased cellular delivery rate, sustained drug release and improved pharmacodynamics, but also synergistically and selectively augmented apoptosis induction in 8 various cancer cell lines, but not in normal cells. The related molecular mechanisms are involved in the concomitant upregulation of DR5 and suppression of anti-apoptotic factors including cFLIP, MCL-1, BCL-2 and IAPs and the NF-kappaB pathway. Additionally, SD9@EV-T was in vivo tested for anti-cancer therapeutic efficacy in a subcutaneous A549 xenograft lung tumor model. The SD9@EV-T therapy demonstrated strikingly promoted efficacy than the SD9 alone treatment, and no evident adverse drug events (ADEs) were observed. In conclusion, the SD9@EV-T nanodrug potentially constitutes a novel and highly effective anti-cancer therapy. |
| format | Article |
| id | doaj-art-76635e6d7f5145acabeb3041b73b92e5 |
| institution | Kabale University |
| issn | 1868-6958 1868-6966 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Nanotechnology |
| spelling | doaj-art-76635e6d7f5145acabeb3041b73b92e52025-08-20T03:45:11ZengBMCCancer Nanotechnology1868-69581868-69662025-06-0116112010.1186/s12645-025-00329-yExosomal encapsulation of a steviol derivative SD9 to overcome TRAIL resistance as a highly effective therapy against lung cancerQuanjiang Li0Yufeng Xie1Wanting Zhang2Jun Peng3Zhujie Deng4Rui Tian5Xiubin Kuang6Bin Xie7Chen Huang8Yu Zhao9Zhengqiang Yuan10School of Biomedical and Pharmaceutical Sciences, Guangdong University of TechnologySchool of Biomedical and Pharmaceutical Sciences, Guangdong University of TechnologySchool of Biomedical and Pharmaceutical Sciences, Guangdong University of TechnologySchool of Biomedical and Pharmaceutical Sciences, Guangdong University of TechnologySchool of Biomedical and Pharmaceutical Sciences, Guangdong University of TechnologySchool of Biomedical and Pharmaceutical Sciences, Guangdong University of TechnologySchool of Biomedical and Pharmaceutical Sciences, Guangdong University of TechnologySchool of Biomedical and Pharmaceutical Sciences, Guangdong University of TechnologyThe Affiliated Panyu Central Hospital of Guangzhou Medical UniversitySchool of Biomedical and Pharmaceutical Sciences, Guangdong University of TechnologySchool of Biomedical and Pharmaceutical Sciences, Guangdong University of TechnologyAbstract Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising pro-apoptotic factor. However, it has showed very limited efficacies due to low bioavailability and common drug resistance in cancers. Extracellular vesicle delivery of TRAIL (EV-T) has significantly improved the activity and the combination of EV-T with some intrinsic apoptosis-inducing chemical compounds showed further strikingly augmented apoptosis induction in cancers. Previously we synthesized a steviol derivative 9# (SD9) that induced intrinsic apoptosis in cancer cells. However, it has never been examined if SD9 collaborates with EV-T to trigger synergistic apoptosis-induction in cancer cells. Herein, we propose that SD9 may be loaded into EV-T to sensitize TRAIL response for a synergistic anti-cancer therapy. First, TRAIL-transduced mesenchymal stem cells (MSCs) were used to produce EV-Ts. Then SD9 was encapsulated into EV-Ts to prepare the complexed nanodrug SD9@EV-T. The encapsulation of SD9 resulted in not only increased cellular delivery rate, sustained drug release and improved pharmacodynamics, but also synergistically and selectively augmented apoptosis induction in 8 various cancer cell lines, but not in normal cells. The related molecular mechanisms are involved in the concomitant upregulation of DR5 and suppression of anti-apoptotic factors including cFLIP, MCL-1, BCL-2 and IAPs and the NF-kappaB pathway. Additionally, SD9@EV-T was in vivo tested for anti-cancer therapeutic efficacy in a subcutaneous A549 xenograft lung tumor model. The SD9@EV-T therapy demonstrated strikingly promoted efficacy than the SD9 alone treatment, and no evident adverse drug events (ADEs) were observed. In conclusion, the SD9@EV-T nanodrug potentially constitutes a novel and highly effective anti-cancer therapy.https://doi.org/10.1186/s12645-025-00329-ySteviol derivativeEV-TComplexed nanodrugTRAIL sensitizationApoptosis |
| spellingShingle | Quanjiang Li Yufeng Xie Wanting Zhang Jun Peng Zhujie Deng Rui Tian Xiubin Kuang Bin Xie Chen Huang Yu Zhao Zhengqiang Yuan Exosomal encapsulation of a steviol derivative SD9 to overcome TRAIL resistance as a highly effective therapy against lung cancer Cancer Nanotechnology Steviol derivative EV-T Complexed nanodrug TRAIL sensitization Apoptosis |
| title | Exosomal encapsulation of a steviol derivative SD9 to overcome TRAIL resistance as a highly effective therapy against lung cancer |
| title_full | Exosomal encapsulation of a steviol derivative SD9 to overcome TRAIL resistance as a highly effective therapy against lung cancer |
| title_fullStr | Exosomal encapsulation of a steviol derivative SD9 to overcome TRAIL resistance as a highly effective therapy against lung cancer |
| title_full_unstemmed | Exosomal encapsulation of a steviol derivative SD9 to overcome TRAIL resistance as a highly effective therapy against lung cancer |
| title_short | Exosomal encapsulation of a steviol derivative SD9 to overcome TRAIL resistance as a highly effective therapy against lung cancer |
| title_sort | exosomal encapsulation of a steviol derivative sd9 to overcome trail resistance as a highly effective therapy against lung cancer |
| topic | Steviol derivative EV-T Complexed nanodrug TRAIL sensitization Apoptosis |
| url | https://doi.org/10.1186/s12645-025-00329-y |
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