In Situ Transformable Nanoparticle Effectively Suppresses Bladder Cancer by Damaging Mitochondria and Blocking Mitochondrial Autophagy Flux
Abstract Tumor therapeutic strategies based on mitochondrial damage have become an emerging trend. However, the low drug delivery efficiency caused by lysosomal sequestration and the activation of protective mitochondrial autophagy severely restricts the therapeutic efficacy. Herein, an in situ tran...
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| Format: | Article |
| Language: | English |
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Wiley
2025-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202409425 |
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| author | Yulin Lv Benli Song Guang Yang Yuting Wang Zeyu Wu Minggui Si Zongzheng Yang Huilin Chen Chen Liu Min Li Yinshi Zhang Zengying Qiao Lu Wang Wanhai Xu |
| author_facet | Yulin Lv Benli Song Guang Yang Yuting Wang Zeyu Wu Minggui Si Zongzheng Yang Huilin Chen Chen Liu Min Li Yinshi Zhang Zengying Qiao Lu Wang Wanhai Xu |
| author_sort | Yulin Lv |
| collection | DOAJ |
| description | Abstract Tumor therapeutic strategies based on mitochondrial damage have become an emerging trend. However, the low drug delivery efficiency caused by lysosomal sequestration and the activation of protective mitochondrial autophagy severely restricts the therapeutic efficacy. Herein, an in situ transformable nanoparticle named KCKT is developed to promote lysosomal escape and directly damage mitochondria while blocking mitochondrial autophagy. KCKT exhibits acid responsiveness for precise self‐assembly into nanofibers within the lysosomes of cancer cells. The massive accumulation of nanofibers and excessive production of reactive oxygen species (ROS) under sonodynamic therapy synergistically induce lysosomal damage. This facilitates the escape of nanofibers from lysosomal sequestration, thereby enhancing drug delivery. Subsequently, the escaped nanofibers specifically aggregate around the mitochondria for long‐term retention and generate ROS under ultrasound irradiation to induce mitochondrial damage. Notably, due to lysosomal dysfunction, damaged mitochondria cannot be cleared by autophagy, further aggravating oxidative damage. These results reveal that KCKT effectively improves drug delivery and mitochondria‐targeted therapy efficiency by blocking protective autophagy. These findings hold significant potential for advancing the field of mitochondria‐targeted therapy. |
| format | Article |
| id | doaj-art-6eed0ac988d54429a459e1b673ccaba4 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-6eed0ac988d54429a459e1b673ccaba42025-02-04T13:14:54ZengWileyAdvanced Science2198-38442025-02-01125n/an/a10.1002/advs.202409425In Situ Transformable Nanoparticle Effectively Suppresses Bladder Cancer by Damaging Mitochondria and Blocking Mitochondrial Autophagy FluxYulin Lv0Benli Song1Guang Yang2Yuting Wang3Zeyu Wu4Minggui Si5Zongzheng Yang6Huilin Chen7Chen Liu8Min Li9Yinshi Zhang10Zengying Qiao11Lu Wang12Wanhai Xu13NHC Key Laboratory of Molecular Probes and Targeted Theranostics Harbin Medical University Harbin 150001 ChinaCAS Center for Excellence in Nanoscience CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety National Center for Nanoscience and Technology (NCNST) No. 11 Beiyitiao Zhongguancun Beijing 100190 ChinaDepartment of Neurosurger The First Affiliated Hospital of Harbin Medical University Harbin 150001 ChinaNHC Key Laboratory of Molecular Probes and Targeted Theranostics Harbin Medical University Harbin 150001 ChinaNHC Key Laboratory of Molecular Probes and Targeted Theranostics Harbin Medical University Harbin 150001 ChinaNHC Key Laboratory of Molecular Probes and Targeted Theranostics Harbin Medical University Harbin 150001 ChinaNHC Key Laboratory of Molecular Probes and Targeted Theranostics Harbin Medical University Harbin 150001 ChinaNHC Key Laboratory of Molecular Probes and Targeted Theranostics Harbin Medical University Harbin 150001 ChinaNHC Key Laboratory of Molecular Probes and Targeted Theranostics Harbin Medical University Harbin 150001 ChinaNHC Key Laboratory of Molecular Probes and Targeted Theranostics Harbin Medical University Harbin 150001 ChinaNHC Key Laboratory of Molecular Probes and Targeted Theranostics Harbin Medical University Harbin 150001 ChinaCAS Center for Excellence in Nanoscience CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety National Center for Nanoscience and Technology (NCNST) No. 11 Beiyitiao Zhongguancun Beijing 100190 ChinaNHC Key Laboratory of Molecular Probes and Targeted Theranostics Harbin Medical University Harbin 150001 ChinaNHC Key Laboratory of Molecular Probes and Targeted Theranostics Harbin Medical University Harbin 150001 ChinaAbstract Tumor therapeutic strategies based on mitochondrial damage have become an emerging trend. However, the low drug delivery efficiency caused by lysosomal sequestration and the activation of protective mitochondrial autophagy severely restricts the therapeutic efficacy. Herein, an in situ transformable nanoparticle named KCKT is developed to promote lysosomal escape and directly damage mitochondria while blocking mitochondrial autophagy. KCKT exhibits acid responsiveness for precise self‐assembly into nanofibers within the lysosomes of cancer cells. The massive accumulation of nanofibers and excessive production of reactive oxygen species (ROS) under sonodynamic therapy synergistically induce lysosomal damage. This facilitates the escape of nanofibers from lysosomal sequestration, thereby enhancing drug delivery. Subsequently, the escaped nanofibers specifically aggregate around the mitochondria for long‐term retention and generate ROS under ultrasound irradiation to induce mitochondrial damage. Notably, due to lysosomal dysfunction, damaged mitochondria cannot be cleared by autophagy, further aggravating oxidative damage. These results reveal that KCKT effectively improves drug delivery and mitochondria‐targeted therapy efficiency by blocking protective autophagy. These findings hold significant potential for advancing the field of mitochondria‐targeted therapy.https://doi.org/10.1002/advs.202409425lysosomal escapemitochondria damagemitochondrial autophagyself‐assemblysonodynamic therapy |
| spellingShingle | Yulin Lv Benli Song Guang Yang Yuting Wang Zeyu Wu Minggui Si Zongzheng Yang Huilin Chen Chen Liu Min Li Yinshi Zhang Zengying Qiao Lu Wang Wanhai Xu In Situ Transformable Nanoparticle Effectively Suppresses Bladder Cancer by Damaging Mitochondria and Blocking Mitochondrial Autophagy Flux Advanced Science lysosomal escape mitochondria damage mitochondrial autophagy self‐assembly sonodynamic therapy |
| title | In Situ Transformable Nanoparticle Effectively Suppresses Bladder Cancer by Damaging Mitochondria and Blocking Mitochondrial Autophagy Flux |
| title_full | In Situ Transformable Nanoparticle Effectively Suppresses Bladder Cancer by Damaging Mitochondria and Blocking Mitochondrial Autophagy Flux |
| title_fullStr | In Situ Transformable Nanoparticle Effectively Suppresses Bladder Cancer by Damaging Mitochondria and Blocking Mitochondrial Autophagy Flux |
| title_full_unstemmed | In Situ Transformable Nanoparticle Effectively Suppresses Bladder Cancer by Damaging Mitochondria and Blocking Mitochondrial Autophagy Flux |
| title_short | In Situ Transformable Nanoparticle Effectively Suppresses Bladder Cancer by Damaging Mitochondria and Blocking Mitochondrial Autophagy Flux |
| title_sort | in situ transformable nanoparticle effectively suppresses bladder cancer by damaging mitochondria and blocking mitochondrial autophagy flux |
| topic | lysosomal escape mitochondria damage mitochondrial autophagy self‐assembly sonodynamic therapy |
| url | https://doi.org/10.1002/advs.202409425 |
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