Reactive oxygen species responsive nanomotors for gene edited metabolic disruption and immunotherapy
Abstract While gene-editing-based tumor therapy holds promise, conventional passive-diffusion vectors face limited penetration in dense solid tumors. Here, we developed a ROS-driven gene editing nanomotor (RDN@PL), which takes hemin as the core and encapsulates CRISPR/Cas9 plasmids targeting LDHA (A...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59590-9 |
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| author | Zhiyong Liu Xiaowei Luan Qianglan Lu Shurong Qin Fei Zeng Zhi Li Bangshun He Yujun Song |
| author_facet | Zhiyong Liu Xiaowei Luan Qianglan Lu Shurong Qin Fei Zeng Zhi Li Bangshun He Yujun Song |
| author_sort | Zhiyong Liu |
| collection | DOAJ |
| description | Abstract While gene-editing-based tumor therapy holds promise, conventional passive-diffusion vectors face limited penetration in dense solid tumors. Here, we developed a ROS-driven gene editing nanomotor (RDN@PL), which takes hemin as the core and encapsulates CRISPR/Cas9 plasmids targeting LDHA (A glycolysis key enzyme). In tumor microenvironments, RDN@PL consumes extracellular ROS to fuel self-diffusiophoresis, achieving higher intratumoral accumulation than passive particles. Upon internalization, heme oxygenase-1 (HO-1) degrades RDN@PL, releasing CO and plasmids. LDHA knockout suppresses glycolysis while CO elevates mitochondrial ROS, which triggers apoptosis by disrupting metabolism and enhancing immunity. Simultaneously, extracellular ROS depletion by non-internalized nanomotors reverses immunogenic cell death (ICD) inhibition, enhancing CD8+ T cell infiltration in tumor. The Janus nanomotor enables extracellular ROS scavenging and intracellular ROS increment via HO-1-responsive cargo release and gene editing. This multi-level intervention strategy demonstrates 93.9 % tumor growth suppression in solid tumor models, providing a blueprint for engineering intelligent nanovesicles in precision oncology. |
| format | Article |
| id | doaj-art-c8c80c83ddc04bd4a2375213b8ea6f14 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c8c80c83ddc04bd4a2375213b8ea6f142025-08-20T03:47:16ZengNature PortfolioNature Communications2041-17232025-05-0116111710.1038/s41467-025-59590-9Reactive oxygen species responsive nanomotors for gene edited metabolic disruption and immunotherapyZhiyong Liu0Xiaowei Luan1Qianglan Lu2Shurong Qin3Fei Zeng4Zhi Li5Bangshun He6Yujun Song7Department of Gastric and Hernia Surgery, Nanjing Drum Tower Hospital, College of Engineering and Applied Sciences, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing UniversityDepartment of Gastric and Hernia Surgery, Nanjing Drum Tower Hospital, College of Engineering and Applied Sciences, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing UniversityDepartment of Gastric and Hernia Surgery, Nanjing Drum Tower Hospital, College of Engineering and Applied Sciences, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing UniversityDepartment of Gastric and Hernia Surgery, Nanjing Drum Tower Hospital, College of Engineering and Applied Sciences, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing UniversityDepartment of Gastric and Hernia Surgery, Nanjing Drum Tower Hospital, College of Engineering and Applied Sciences, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing UniversityDepartment of Gastric and Hernia Surgery, Nanjing Drum Tower Hospital, College of Engineering and Applied Sciences, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing UniversityDepartment of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical UniversityDepartment of Gastric and Hernia Surgery, Nanjing Drum Tower Hospital, College of Engineering and Applied Sciences, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing UniversityAbstract While gene-editing-based tumor therapy holds promise, conventional passive-diffusion vectors face limited penetration in dense solid tumors. Here, we developed a ROS-driven gene editing nanomotor (RDN@PL), which takes hemin as the core and encapsulates CRISPR/Cas9 plasmids targeting LDHA (A glycolysis key enzyme). In tumor microenvironments, RDN@PL consumes extracellular ROS to fuel self-diffusiophoresis, achieving higher intratumoral accumulation than passive particles. Upon internalization, heme oxygenase-1 (HO-1) degrades RDN@PL, releasing CO and plasmids. LDHA knockout suppresses glycolysis while CO elevates mitochondrial ROS, which triggers apoptosis by disrupting metabolism and enhancing immunity. Simultaneously, extracellular ROS depletion by non-internalized nanomotors reverses immunogenic cell death (ICD) inhibition, enhancing CD8+ T cell infiltration in tumor. The Janus nanomotor enables extracellular ROS scavenging and intracellular ROS increment via HO-1-responsive cargo release and gene editing. This multi-level intervention strategy demonstrates 93.9 % tumor growth suppression in solid tumor models, providing a blueprint for engineering intelligent nanovesicles in precision oncology.https://doi.org/10.1038/s41467-025-59590-9 |
| spellingShingle | Zhiyong Liu Xiaowei Luan Qianglan Lu Shurong Qin Fei Zeng Zhi Li Bangshun He Yujun Song Reactive oxygen species responsive nanomotors for gene edited metabolic disruption and immunotherapy Nature Communications |
| title | Reactive oxygen species responsive nanomotors for gene edited metabolic disruption and immunotherapy |
| title_full | Reactive oxygen species responsive nanomotors for gene edited metabolic disruption and immunotherapy |
| title_fullStr | Reactive oxygen species responsive nanomotors for gene edited metabolic disruption and immunotherapy |
| title_full_unstemmed | Reactive oxygen species responsive nanomotors for gene edited metabolic disruption and immunotherapy |
| title_short | Reactive oxygen species responsive nanomotors for gene edited metabolic disruption and immunotherapy |
| title_sort | reactive oxygen species responsive nanomotors for gene edited metabolic disruption and immunotherapy |
| url | https://doi.org/10.1038/s41467-025-59590-9 |
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