Mevalonate pathway-triggered phase transition of injectable hydrogel for cholesterol-downregulated therapy of osteoarthritis
Dysregulation of mevalonate pathway, an essential metabolic route involving coenzyme A (CoASH) and cholesterol, contributes significantly to escalating cartilage degradation. Existing treatments rely on the simvastatin delivery via tunable sol-gel transition mechanisms of injectable hydrogel. Howeve...
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| Format: | Article |
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KeAi Communications Co., Ltd.
2025-09-01
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| Series: | Bioactive Materials |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2452199X2500283X |
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| author | Akhmad Irhas Robby Ee Hyun Kim Kang Moo Huh Eun-Jung Jin Ki Dong Park Sung Young Park |
| author_facet | Akhmad Irhas Robby Ee Hyun Kim Kang Moo Huh Eun-Jung Jin Ki Dong Park Sung Young Park |
| author_sort | Akhmad Irhas Robby |
| collection | DOAJ |
| description | Dysregulation of mevalonate pathway, an essential metabolic route involving coenzyme A (CoASH) and cholesterol, contributes significantly to escalating cartilage degradation. Existing treatments rely on the simvastatin delivery via tunable sol-gel transition mechanisms of injectable hydrogel. However, those methods suffer from lack of controllable drug release by selective phase transition under distinct disease microenvironment. Herein, we developed an aberrant lipid metabolism microenvironment-activated phase transition (normal condition: gel-gel, abnormal condition: gel-sol) with targeted drug release for synergistic treatment of osteoarthritis (OA). Naked-eye diagnosis and therapy of OA through cholesterol downregulation using an injectable hydrogel were based on the simvastatin-loaded nanoparticles embedded in hexanoyl glycol chitosan (HGC-SIM@PAA-MnO2-cPDA or SIM gel). The interaction between highly expressed CoASH in OA and PAA-MnO2 in SIM gel altered the hydrophobic–hydrophilic balance and gelation temperature, triggering the OA-sensitive gel-sol transformation. Naked-eye gel-sol transformation was observed after incubating SIM gel with OA chondrocyte models, including acetyl-CoA-induced wild-type (WT + CoA), NudT7−/− knockout (N7KO), and Acot12−/− knockout (A12KO). Because of the simvastatin release after gel-sol transition, OA-related enzymes and genes, including antioxidant enzymes (Sod2), cartilage degradation genes (Adamts4), and cholesterol synthesis-related enzymes (Mvk), were downregulated. In vivo studies revealed gel-sol transformation in destabilized medial meniscus of OA mice (DMM WT, N7KO, and A12KO) at 4–8 weeks post-injection, with significantly reduced cartilage degradation, demonstrating theragnostic capability of SIM gel. Thus, SIM gel offers a potential approach for future synergistic OA diagnosis and therapy. |
| format | Article |
| id | doaj-art-380eab2e16c04b75a25f3b5f47eabe26 |
| institution | Kabale University |
| issn | 2452-199X |
| language | English |
| publishDate | 2025-09-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Bioactive Materials |
| spelling | doaj-art-380eab2e16c04b75a25f3b5f47eabe262025-08-20T03:57:31ZengKeAi Communications Co., Ltd.Bioactive Materials2452-199X2025-09-015187688810.1016/j.bioactmat.2025.06.047Mevalonate pathway-triggered phase transition of injectable hydrogel for cholesterol-downregulated therapy of osteoarthritisAkhmad Irhas Robby0Ee Hyun Kim1Kang Moo Huh2Eun-Jung Jin3Ki Dong Park4Sung Young Park5Chemical Industry Institute, Korea National University of Transportation, Chungju, 27469, Republic of Korea; Department of Chemical & Biological Engineering, Korea National University of Transportation, Chungju, 27469, Republic of KoreaDepartment of Biomedical Materials Science, Graduate School of JABA, Wonkwang University, Iksan, Jeonbuk State, 54538, Republic of KoreaDepartment of Polymer Science and Engineering, Chungnam National University, Daejeon, 305-764, Republic of Korea; Corresponding authors.Department of Biomedical Materials Science, Graduate School of JABA, Wonkwang University, Iksan, Jeonbuk State, 54538, Republic of Korea; Corresponding author.Department of Molecular Science and Technology, Ajou University, Woncheon, Yeongtong, Suwon, 443-749, Republic of Korea; Corresponding authors.Chemical Industry Institute, Korea National University of Transportation, Chungju, 27469, Republic of Korea; Department of Chemical & Biological Engineering, Korea National University of Transportation, Chungju, 27469, Republic of Korea; Corresponding author. Chemical Industry Institute, Korea National University of Transportation, Chungju, 27469, Republic of Korea.Dysregulation of mevalonate pathway, an essential metabolic route involving coenzyme A (CoASH) and cholesterol, contributes significantly to escalating cartilage degradation. Existing treatments rely on the simvastatin delivery via tunable sol-gel transition mechanisms of injectable hydrogel. However, those methods suffer from lack of controllable drug release by selective phase transition under distinct disease microenvironment. Herein, we developed an aberrant lipid metabolism microenvironment-activated phase transition (normal condition: gel-gel, abnormal condition: gel-sol) with targeted drug release for synergistic treatment of osteoarthritis (OA). Naked-eye diagnosis and therapy of OA through cholesterol downregulation using an injectable hydrogel were based on the simvastatin-loaded nanoparticles embedded in hexanoyl glycol chitosan (HGC-SIM@PAA-MnO2-cPDA or SIM gel). The interaction between highly expressed CoASH in OA and PAA-MnO2 in SIM gel altered the hydrophobic–hydrophilic balance and gelation temperature, triggering the OA-sensitive gel-sol transformation. Naked-eye gel-sol transformation was observed after incubating SIM gel with OA chondrocyte models, including acetyl-CoA-induced wild-type (WT + CoA), NudT7−/− knockout (N7KO), and Acot12−/− knockout (A12KO). Because of the simvastatin release after gel-sol transition, OA-related enzymes and genes, including antioxidant enzymes (Sod2), cartilage degradation genes (Adamts4), and cholesterol synthesis-related enzymes (Mvk), were downregulated. In vivo studies revealed gel-sol transformation in destabilized medial meniscus of OA mice (DMM WT, N7KO, and A12KO) at 4–8 weeks post-injection, with significantly reduced cartilage degradation, demonstrating theragnostic capability of SIM gel. Thus, SIM gel offers a potential approach for future synergistic OA diagnosis and therapy.http://www.sciencedirect.com/science/article/pii/S2452199X2500283XOsteoarthritisInjectable hydrogelCoenzyme AMevalonate pathwayTheragnostic |
| spellingShingle | Akhmad Irhas Robby Ee Hyun Kim Kang Moo Huh Eun-Jung Jin Ki Dong Park Sung Young Park Mevalonate pathway-triggered phase transition of injectable hydrogel for cholesterol-downregulated therapy of osteoarthritis Bioactive Materials Osteoarthritis Injectable hydrogel Coenzyme A Mevalonate pathway Theragnostic |
| title | Mevalonate pathway-triggered phase transition of injectable hydrogel for cholesterol-downregulated therapy of osteoarthritis |
| title_full | Mevalonate pathway-triggered phase transition of injectable hydrogel for cholesterol-downregulated therapy of osteoarthritis |
| title_fullStr | Mevalonate pathway-triggered phase transition of injectable hydrogel for cholesterol-downregulated therapy of osteoarthritis |
| title_full_unstemmed | Mevalonate pathway-triggered phase transition of injectable hydrogel for cholesterol-downregulated therapy of osteoarthritis |
| title_short | Mevalonate pathway-triggered phase transition of injectable hydrogel for cholesterol-downregulated therapy of osteoarthritis |
| title_sort | mevalonate pathway triggered phase transition of injectable hydrogel for cholesterol downregulated therapy of osteoarthritis |
| topic | Osteoarthritis Injectable hydrogel Coenzyme A Mevalonate pathway Theragnostic |
| url | http://www.sciencedirect.com/science/article/pii/S2452199X2500283X |
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