Targeted codelivery of nitric oxide and hydrogen sulfide for enhanced antithrombosis efficacy
Thrombosis is a leading cause of mortality worldwide. As important gaseous signaling molecules, both nitric oxide (NO) and hydrogen sulfide (H2S) demonstrate antiplatelet and anticoagulant functions, but little attention has been given to their synergistic effect and the underlying mechanism. In the...
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KeAi Communications Co., Ltd.
2025-06-01
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| author | Weiliang Deng Zhixin Xu Tong Hua Guangbo Ji Zihang Wang Pei Liu Yupeng Zhang Shuo Li Yuqiu Chao Meng Qian Qiang Zhao Jinwei Tian |
| author_facet | Weiliang Deng Zhixin Xu Tong Hua Guangbo Ji Zihang Wang Pei Liu Yupeng Zhang Shuo Li Yuqiu Chao Meng Qian Qiang Zhao Jinwei Tian |
| author_sort | Weiliang Deng |
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| description | Thrombosis is a leading cause of mortality worldwide. As important gaseous signaling molecules, both nitric oxide (NO) and hydrogen sulfide (H2S) demonstrate antiplatelet and anticoagulant functions, but little attention has been given to their synergistic effect and the underlying mechanism. In the present study, we developed an NO/H2S codelivery system based on enzyme prodrug therapy (EPT) strategy in which the prodrugs are specifically recognized by the engineered β-galactosidase. Targeted codelivery of NO and H2S in vivo was demonstrated by near-infrared fluorescence imaging and confirmed by measuring plasma and tissue levels; as a result, the side effects caused by systemic delivery, such as bleeding time, were reduced. Delivery of an optimized combination of NO and H2S with a low combination index (CI) results in a synergistic effect on the inhibition of platelet adhesion and activation. Mechanistically, NO and H2S cooperatively enhance the cGMP level through redox-based posttranslational modifications of phosphodiesterase 5A (PDE5A), which leads to activation of the cGMP/PKG signaling pathway. Furthermore, targeted codelivery of NO and H2S demonstrates enhanced therapeutic efficacy for thrombosis in two mouse models of FeCl3-induced arterial thrombosis and deep vein thrombosis. Collectively, these results confirm the synergistic efficacy of NO and H2S for antithrombotic therapy, and the codelivery system developed in this study represents a promising candidate for clinical translation. |
| format | Article |
| id | doaj-art-dcbddbf55c4f4d73af4a6292017edd73 |
| institution | OA Journals |
| issn | 2452-199X |
| language | English |
| publishDate | 2025-06-01 |
| publisher | KeAi Communications Co., Ltd. |
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| series | Bioactive Materials |
| spelling | doaj-art-dcbddbf55c4f4d73af4a6292017edd732025-08-20T02:12:10ZengKeAi Communications Co., Ltd.Bioactive Materials2452-199X2025-06-0148294210.1016/j.bioactmat.2025.02.012Targeted codelivery of nitric oxide and hydrogen sulfide for enhanced antithrombosis efficacyWeiliang Deng0Zhixin Xu1Tong Hua2Guangbo Ji3Zihang Wang4Pei Liu5Yupeng Zhang6Shuo Li7Yuqiu Chao8Meng Qian9Qiang Zhao10Jinwei Tian11State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, 300071, ChinaState Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, 300071, ChinaState Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, 300071, ChinaState Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, 300071, ChinaDepartment of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Heilongjiang Provincial Key Laboratory of Panvascular Disease, Harbin, 150086, ChinaState Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, 300071, ChinaState Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, 300071, ChinaDepartment of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Heilongjiang Provincial Key Laboratory of Panvascular Disease, Harbin, 150086, ChinaDepartment of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Heilongjiang Provincial Key Laboratory of Panvascular Disease, Harbin, 150086, ChinaState Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, 300071, China; Corresponding author.State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, 300071, China; The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Health Science Center, Peking University, Beijing, 100191, China; Corresponding author. State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, 300071, China.Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Heilongjiang Provincial Key Laboratory of Panvascular Disease, Harbin, 150086, China; Corresponding author.Thrombosis is a leading cause of mortality worldwide. As important gaseous signaling molecules, both nitric oxide (NO) and hydrogen sulfide (H2S) demonstrate antiplatelet and anticoagulant functions, but little attention has been given to their synergistic effect and the underlying mechanism. In the present study, we developed an NO/H2S codelivery system based on enzyme prodrug therapy (EPT) strategy in which the prodrugs are specifically recognized by the engineered β-galactosidase. Targeted codelivery of NO and H2S in vivo was demonstrated by near-infrared fluorescence imaging and confirmed by measuring plasma and tissue levels; as a result, the side effects caused by systemic delivery, such as bleeding time, were reduced. Delivery of an optimized combination of NO and H2S with a low combination index (CI) results in a synergistic effect on the inhibition of platelet adhesion and activation. Mechanistically, NO and H2S cooperatively enhance the cGMP level through redox-based posttranslational modifications of phosphodiesterase 5A (PDE5A), which leads to activation of the cGMP/PKG signaling pathway. Furthermore, targeted codelivery of NO and H2S demonstrates enhanced therapeutic efficacy for thrombosis in two mouse models of FeCl3-induced arterial thrombosis and deep vein thrombosis. Collectively, these results confirm the synergistic efficacy of NO and H2S for antithrombotic therapy, and the codelivery system developed in this study represents a promising candidate for clinical translation.http://www.sciencedirect.com/science/article/pii/S2452199X2500060XNitric oxideHydrogen sulfidePrecise deliverySynergistic effectThrombosis |
| spellingShingle | Weiliang Deng Zhixin Xu Tong Hua Guangbo Ji Zihang Wang Pei Liu Yupeng Zhang Shuo Li Yuqiu Chao Meng Qian Qiang Zhao Jinwei Tian Targeted codelivery of nitric oxide and hydrogen sulfide for enhanced antithrombosis efficacy Bioactive Materials Nitric oxide Hydrogen sulfide Precise delivery Synergistic effect Thrombosis |
| title | Targeted codelivery of nitric oxide and hydrogen sulfide for enhanced antithrombosis efficacy |
| title_full | Targeted codelivery of nitric oxide and hydrogen sulfide for enhanced antithrombosis efficacy |
| title_fullStr | Targeted codelivery of nitric oxide and hydrogen sulfide for enhanced antithrombosis efficacy |
| title_full_unstemmed | Targeted codelivery of nitric oxide and hydrogen sulfide for enhanced antithrombosis efficacy |
| title_short | Targeted codelivery of nitric oxide and hydrogen sulfide for enhanced antithrombosis efficacy |
| title_sort | targeted codelivery of nitric oxide and hydrogen sulfide for enhanced antithrombosis efficacy |
| topic | Nitric oxide Hydrogen sulfide Precise delivery Synergistic effect Thrombosis |
| url | http://www.sciencedirect.com/science/article/pii/S2452199X2500060X |
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