An exosome-based nanoplatform for siRNA delivery combined with starvation therapy promotes tumor cell death through autophagy, overcoming refractory KRAS-mutated tumors and restoring cetuximab chemosensitivity
Multi-drug combination therapy is one of the most effective strategies for the treatment of drug-resistant and advanced tumors. Modern nanodrug delivery systems are crucial for multi-drug combination therapy and gene therapy. However, research on direct injection of RNAi has not yielded significant...
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Elsevier
2025-06-01
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| Series: | Materials Today Bio |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2590006425002911 |
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| author | Yurong Xiang Qiang Liu Kang Liu Liuxian Chen Fengjiao Chen Tao Li Siqi Li Qiang Yu Quan Lv Zheng Xiang |
| author_facet | Yurong Xiang Qiang Liu Kang Liu Liuxian Chen Fengjiao Chen Tao Li Siqi Li Qiang Yu Quan Lv Zheng Xiang |
| author_sort | Yurong Xiang |
| collection | DOAJ |
| description | Multi-drug combination therapy is one of the most effective strategies for the treatment of drug-resistant and advanced tumors. Modern nanodrug delivery systems are crucial for multi-drug combination therapy and gene therapy. However, research on direct injection of RNAi has not yielded significant results. Artificial vectors are emerging as promising delivery systemts for RNA for gene therapy. In this study, a multi-drug therapy system was built based on a biodegradable exosome nano-platform exploiting the protective and low immunogenic properties of exosomes for RNA. This work aimed to accomplish the co-delivery of siRNA and 3-Bromopyruvic acid (3BP) on an exosome nanoplatform, enhancing targeting by coupling cetuximab (CTX) to exosome membranes, resulting in a new nanomedicine Exo@siRNA/3BP-CTX (ERBC) engineered exosomes. The synthesis conditions were optimized to obtain stable, safe, and effective nanomedicines. Successful targeting of tumors with CTX inhibited KRAS oncogene expression and significantly reduced glucose uptake by cancer cells. This enhanced the starvation therapy effect of the energy deprivation agent 3BP, thus promoting excessive autophagy activation in cells and doubling apoptosis. However, ERBC combined with CTX therapy restored cellular chemosensitivity to CTX. These findings indicate that engineered exosomes with dual therapeutic activities is a promising approach for treating refractory KRAS-mutant cancers. |
| format | Article |
| id | doaj-art-23b9cd7e23244922bdb1da04c0dcc82f |
| institution | OA Journals |
| issn | 2590-0064 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Materials Today Bio |
| spelling | doaj-art-23b9cd7e23244922bdb1da04c0dcc82f2025-08-20T02:11:54ZengElsevierMaterials Today Bio2590-00642025-06-013210173210.1016/j.mtbio.2025.101732An exosome-based nanoplatform for siRNA delivery combined with starvation therapy promotes tumor cell death through autophagy, overcoming refractory KRAS-mutated tumors and restoring cetuximab chemosensitivityYurong Xiang0Qiang Liu1Kang Liu2Liuxian Chen3Fengjiao Chen4Tao Li5Siqi Li6Qiang Yu7Quan Lv8Zheng Xiang9Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, China; Chongqing Key Laboratory of Department of General Surgery, The First Afiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, ChinaDepartment of Hepatobiliary Surgery, Suining First People's Hospital, 22 Youfang Street, 629000, Suining, ChinaDepartment of Cardiovascular Surgery, Fuwai Yunnan Cardiovascular Hospital, 528 Shahe North Road, 400042, Kunming, ChinaDepartment of Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, No.1 Medical College Road, 400016, Chongqing, ChinaCenter for Clinical Molecular Medical Detection and Biobank, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, ChinaDepartment of Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, No.1 Medical College Road, 400016, Chongqing, ChinaDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, China; Chongqing Key Laboratory of Department of General Surgery, The First Afiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, ChinaDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, China; Chongqing Key Laboratory of Department of General Surgery, The First Afiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, ChinaDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, China; Chongqing Key Laboratory of Department of General Surgery, The First Afiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, ChinaDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, China; Chongqing Key Laboratory of Department of General Surgery, The First Afiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, China; Corresponding author. Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, China.Multi-drug combination therapy is one of the most effective strategies for the treatment of drug-resistant and advanced tumors. Modern nanodrug delivery systems are crucial for multi-drug combination therapy and gene therapy. However, research on direct injection of RNAi has not yielded significant results. Artificial vectors are emerging as promising delivery systemts for RNA for gene therapy. In this study, a multi-drug therapy system was built based on a biodegradable exosome nano-platform exploiting the protective and low immunogenic properties of exosomes for RNA. This work aimed to accomplish the co-delivery of siRNA and 3-Bromopyruvic acid (3BP) on an exosome nanoplatform, enhancing targeting by coupling cetuximab (CTX) to exosome membranes, resulting in a new nanomedicine Exo@siRNA/3BP-CTX (ERBC) engineered exosomes. The synthesis conditions were optimized to obtain stable, safe, and effective nanomedicines. Successful targeting of tumors with CTX inhibited KRAS oncogene expression and significantly reduced glucose uptake by cancer cells. This enhanced the starvation therapy effect of the energy deprivation agent 3BP, thus promoting excessive autophagy activation in cells and doubling apoptosis. However, ERBC combined with CTX therapy restored cellular chemosensitivity to CTX. These findings indicate that engineered exosomes with dual therapeutic activities is a promising approach for treating refractory KRAS-mutant cancers.http://www.sciencedirect.com/science/article/pii/S2590006425002911Colorectal cancerKRAS mutationStarvation therapyExosomeCetuximab chemosensitivity |
| spellingShingle | Yurong Xiang Qiang Liu Kang Liu Liuxian Chen Fengjiao Chen Tao Li Siqi Li Qiang Yu Quan Lv Zheng Xiang An exosome-based nanoplatform for siRNA delivery combined with starvation therapy promotes tumor cell death through autophagy, overcoming refractory KRAS-mutated tumors and restoring cetuximab chemosensitivity Materials Today Bio Colorectal cancer KRAS mutation Starvation therapy Exosome Cetuximab chemosensitivity |
| title | An exosome-based nanoplatform for siRNA delivery combined with starvation therapy promotes tumor cell death through autophagy, overcoming refractory KRAS-mutated tumors and restoring cetuximab chemosensitivity |
| title_full | An exosome-based nanoplatform for siRNA delivery combined with starvation therapy promotes tumor cell death through autophagy, overcoming refractory KRAS-mutated tumors and restoring cetuximab chemosensitivity |
| title_fullStr | An exosome-based nanoplatform for siRNA delivery combined with starvation therapy promotes tumor cell death through autophagy, overcoming refractory KRAS-mutated tumors and restoring cetuximab chemosensitivity |
| title_full_unstemmed | An exosome-based nanoplatform for siRNA delivery combined with starvation therapy promotes tumor cell death through autophagy, overcoming refractory KRAS-mutated tumors and restoring cetuximab chemosensitivity |
| title_short | An exosome-based nanoplatform for siRNA delivery combined with starvation therapy promotes tumor cell death through autophagy, overcoming refractory KRAS-mutated tumors and restoring cetuximab chemosensitivity |
| title_sort | exosome based nanoplatform for sirna delivery combined with starvation therapy promotes tumor cell death through autophagy overcoming refractory kras mutated tumors and restoring cetuximab chemosensitivity |
| topic | Colorectal cancer KRAS mutation Starvation therapy Exosome Cetuximab chemosensitivity |
| url | http://www.sciencedirect.com/science/article/pii/S2590006425002911 |
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