Dual-responsive nanoparticles targeting ACE-II senescence for therapeutic mitigation of acute lung injury
Abstract Acute lung injury (ALI) is a life-threatening condition characterized by severe pulmonary dysfunction, with alveolar type II epithelial cell (ACE-II) senescence playing a pivotal role in its progression. In this study, we developed pH/reactive oxygen species (ROS) dual-responsive nanopartic...
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| Language: | English |
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BMC
2025-05-01
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| Series: | Journal of Nanobiotechnology |
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| Online Access: | https://doi.org/10.1186/s12951-025-03382-2 |
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| author | Linlin Gao Fushuang Zheng Zhiling Fu Wei Wang |
| author_facet | Linlin Gao Fushuang Zheng Zhiling Fu Wei Wang |
| author_sort | Linlin Gao |
| collection | DOAJ |
| description | Abstract Acute lung injury (ALI) is a life-threatening condition characterized by severe pulmonary dysfunction, with alveolar type II epithelial cell (ACE-II) senescence playing a pivotal role in its progression. In this study, we developed pH/reactive oxygen species (ROS) dual-responsive nanoparticles (GNPsanti-SP-C) for the targeted delivery of Growth Differentiation Factor 15 (GDF15) to counteract ACE-II senescence. These nanoparticles (NPs) effectively activate the AMP-activated protein kinase (AMPK)/Sirtuin 1 (SIRT1) signaling pathway, inducing the mitochondrial unfolded protein response (UPRmt) and reversing senescence-associated cellular dysfunction. GNPsanti-SP-C were systematically engineered and demonstrated robust pH/ROS sensitivity, efficient GDF15 release, and precise ACE-II targeting. In lipopolysaccharide (LPS)-induced ALI mouse model, GNPsanti-SP-C treatment significantly mitigated lung injury, reduced inflammatory responses, and enhanced pulmonary function, as evidenced by decreased inflammatory markers, lung edema, and improved histopathology. Single-cell transcriptomic and proteomic analyses revealed increased ACE-II cell populations, reduced expression of senescence markers, and upregulation of AMPK/SIRT1 signaling. In vitro studies further demonstrated that UPRmt activation is associated with the NPs’ therapeutic effects, suggesting a potential role in their mechanism of action. These findings demonstrate the potential of GDF15-loaded dual-responsive NPs as an innovative strategy to address cellular senescence and alleviate ALI-associated pulmonary damage. Graphical abstract |
| format | Article |
| id | doaj-art-7aa642ab3eec4c9a8e097c677d756823 |
| institution | Kabale University |
| issn | 1477-3155 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| series | Journal of Nanobiotechnology |
| spelling | doaj-art-7aa642ab3eec4c9a8e097c677d7568232025-08-20T03:53:13ZengBMCJournal of Nanobiotechnology1477-31552025-05-0123112510.1186/s12951-025-03382-2Dual-responsive nanoparticles targeting ACE-II senescence for therapeutic mitigation of acute lung injuryLinlin Gao0Fushuang Zheng1Zhiling Fu2Wei Wang3Department of Critical Care Medicine, Shengjing Hospital of China Medical UniversityDepartment of Thoracic Surgery, Shengjing Hospital of China Medical UniversityDepartment of Anesthesiology, Shengjing Hospital of China Medical UniversityDepartment of Anesthesiology, Shengjing Hospital of China Medical UniversityAbstract Acute lung injury (ALI) is a life-threatening condition characterized by severe pulmonary dysfunction, with alveolar type II epithelial cell (ACE-II) senescence playing a pivotal role in its progression. In this study, we developed pH/reactive oxygen species (ROS) dual-responsive nanoparticles (GNPsanti-SP-C) for the targeted delivery of Growth Differentiation Factor 15 (GDF15) to counteract ACE-II senescence. These nanoparticles (NPs) effectively activate the AMP-activated protein kinase (AMPK)/Sirtuin 1 (SIRT1) signaling pathway, inducing the mitochondrial unfolded protein response (UPRmt) and reversing senescence-associated cellular dysfunction. GNPsanti-SP-C were systematically engineered and demonstrated robust pH/ROS sensitivity, efficient GDF15 release, and precise ACE-II targeting. In lipopolysaccharide (LPS)-induced ALI mouse model, GNPsanti-SP-C treatment significantly mitigated lung injury, reduced inflammatory responses, and enhanced pulmonary function, as evidenced by decreased inflammatory markers, lung edema, and improved histopathology. Single-cell transcriptomic and proteomic analyses revealed increased ACE-II cell populations, reduced expression of senescence markers, and upregulation of AMPK/SIRT1 signaling. In vitro studies further demonstrated that UPRmt activation is associated with the NPs’ therapeutic effects, suggesting a potential role in their mechanism of action. These findings demonstrate the potential of GDF15-loaded dual-responsive NPs as an innovative strategy to address cellular senescence and alleviate ALI-associated pulmonary damage. Graphical abstracthttps://doi.org/10.1186/s12951-025-03382-2Acute lung injuryNanoparticle therapyGDF15Cellular senescenceAMPK/SIRT1 signalingMitochondrial unfolded protein response |
| spellingShingle | Linlin Gao Fushuang Zheng Zhiling Fu Wei Wang Dual-responsive nanoparticles targeting ACE-II senescence for therapeutic mitigation of acute lung injury Journal of Nanobiotechnology Acute lung injury Nanoparticle therapy GDF15 Cellular senescence AMPK/SIRT1 signaling Mitochondrial unfolded protein response |
| title | Dual-responsive nanoparticles targeting ACE-II senescence for therapeutic mitigation of acute lung injury |
| title_full | Dual-responsive nanoparticles targeting ACE-II senescence for therapeutic mitigation of acute lung injury |
| title_fullStr | Dual-responsive nanoparticles targeting ACE-II senescence for therapeutic mitigation of acute lung injury |
| title_full_unstemmed | Dual-responsive nanoparticles targeting ACE-II senescence for therapeutic mitigation of acute lung injury |
| title_short | Dual-responsive nanoparticles targeting ACE-II senescence for therapeutic mitigation of acute lung injury |
| title_sort | dual responsive nanoparticles targeting ace ii senescence for therapeutic mitigation of acute lung injury |
| topic | Acute lung injury Nanoparticle therapy GDF15 Cellular senescence AMPK/SIRT1 signaling Mitochondrial unfolded protein response |
| url | https://doi.org/10.1186/s12951-025-03382-2 |
| work_keys_str_mv | AT linlingao dualresponsivenanoparticlestargetingaceiisenescencefortherapeuticmitigationofacutelunginjury AT fushuangzheng dualresponsivenanoparticlestargetingaceiisenescencefortherapeuticmitigationofacutelunginjury AT zhilingfu dualresponsivenanoparticlestargetingaceiisenescencefortherapeuticmitigationofacutelunginjury AT weiwang dualresponsivenanoparticlestargetingaceiisenescencefortherapeuticmitigationofacutelunginjury |