Promotion of NLRP3 autophagosome degradation by PV-K nanodevice for protection against macrophage pyroptosis-mediated lung injury
Abstract Acute respiratory distress syndrome (ARDS) has emerged as a significant global health challenge, with no definitive curative treatment available. Recent evidence suggests that pyroptosis of immune cells plays a pivotal role in the pathogenesis of ARDS. Targeting and modulating immune cell p...
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BMC
2025-02-01
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| Series: | Journal of Nanobiotechnology |
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| Online Access: | https://doi.org/10.1186/s12951-025-03219-y |
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| author | Yan Fan Jian Mei Yuehao Shen Ying Gao Lina Zhao Shuqi Meng Shuai Zhou Yu Qian Ying Zhang Zhiwei Wang Yu Song Jianfeng Liu Shuaijie Pei Yan Cui Hong Yang Shan-Yu Fung Keliang Xie |
| author_facet | Yan Fan Jian Mei Yuehao Shen Ying Gao Lina Zhao Shuqi Meng Shuai Zhou Yu Qian Ying Zhang Zhiwei Wang Yu Song Jianfeng Liu Shuaijie Pei Yan Cui Hong Yang Shan-Yu Fung Keliang Xie |
| author_sort | Yan Fan |
| collection | DOAJ |
| description | Abstract Acute respiratory distress syndrome (ARDS) has emerged as a significant global health challenge, with no definitive curative treatment available. Recent evidence suggests that pyroptosis of immune cells plays a pivotal role in the pathogenesis of ARDS. Targeting and modulating immune cell pyroptosis in lung tissue may offer a promising strategy to mitigate the harmful inflammation associated with this condition. In this study, we designed and synthesized a novel class of peptide-functionalized nanoparticles, PV-K, which possess an intrinsic capacity for phagocytosis by macrophages. Concurrently, the incorporation of two FFD functional groups into a single polypeptide enhances the biological activity of PV-K. Amazingly, PV-K demonstrated potent inhibitory effects on nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3)-mediated pyroptosis in both mouse bone marrow-derived macrophages and the human THP-1 cell-derived macrophages. In both lipopolysaccharide and cecal ligation and puncture induced acute lung injury mouse models, treatment with PV-K significantly reduced disease severity by alleviating pulmonary inflammation and inhibiting macrophage pyroptosis. Transcriptomic analysis revealed that PV-K enhanced SQSM1/p62-mediated autophagy through upregulation of the NRF2 signaling pathway. Mechanistically, PV-K facilitated the interaction between SQSTM1/p62 and NLRP3, promoting the autolysosomal degradation of NLRP3. Notably, the inhibitory effect of PV-K on macrophage pyroptosis during acute lung injury was abrogated in Nrf2 -/- mice. This study introduces a novel nanotherapeutic approach aiming at regulating macrophage pyroptosis by facilitating NLRP3 degradation, thereby controlling inflammation in ARDS/ALI. This strategy may complement existing clinical treatments for ARDS/ALI. |
| format | Article |
| id | doaj-art-e5af85d2d493434f9ac85839b22aa3e6 |
| institution | OA Journals |
| issn | 1477-3155 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj-art-e5af85d2d493434f9ac85839b22aa3e62025-08-20T02:28:04ZengBMCJournal of Nanobiotechnology1477-31552025-02-0123111710.1186/s12951-025-03219-yPromotion of NLRP3 autophagosome degradation by PV-K nanodevice for protection against macrophage pyroptosis-mediated lung injuryYan Fan0Jian Mei1Yuehao Shen2Ying Gao3Lina Zhao4Shuqi Meng5Shuai Zhou6Yu Qian7Ying Zhang8Zhiwei Wang9Yu Song10Jianfeng Liu11Shuaijie Pei12Yan Cui13Hong Yang14Shan-Yu Fung15Keliang Xie16Department of Critical Care Medicine, Tianjin Medical University General HospitalState Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Science, International Joint Laboratory of Ocular Diseases, Ministry of Education, Tianjin Medical UniversityDepartment of Critical Care Medicine, Tianjin Medical University General HospitalDepartment of Critical Care Medicine, Tianjin Medical University General HospitalDepartment of Critical Care Medicine, Tianjin Medical University General HospitalDepartment of Critical Care Medicine, Tianjin Medical University General HospitalDepartment of Critical Care Medicine, Tianjin Medical University General HospitalDepartment of Critical Care Medicine, Tianjin Medical University General HospitalDepartment of Critical Care Medicine, Tianjin Medical University General HospitalDepartment of Critical Care Medicine, Tianjin Medical University General HospitalDepartment of Critical Care Medicine, Tianjin Medical University General HospitalDepartment of Critical Care Medicine, Tianjin Medical University General HospitalDepartment of Critical Care Medicine, Tianjin Medical University General HospitalDepartment of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical UniversityDepartment of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Intensive Care Unit of the Second Hospital, The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical UniversityState Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Science, International Joint Laboratory of Ocular Diseases, Ministry of Education, Tianjin Medical UniversityDepartment of Critical Care Medicine, Tianjin Medical University General HospitalAbstract Acute respiratory distress syndrome (ARDS) has emerged as a significant global health challenge, with no definitive curative treatment available. Recent evidence suggests that pyroptosis of immune cells plays a pivotal role in the pathogenesis of ARDS. Targeting and modulating immune cell pyroptosis in lung tissue may offer a promising strategy to mitigate the harmful inflammation associated with this condition. In this study, we designed and synthesized a novel class of peptide-functionalized nanoparticles, PV-K, which possess an intrinsic capacity for phagocytosis by macrophages. Concurrently, the incorporation of two FFD functional groups into a single polypeptide enhances the biological activity of PV-K. Amazingly, PV-K demonstrated potent inhibitory effects on nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3)-mediated pyroptosis in both mouse bone marrow-derived macrophages and the human THP-1 cell-derived macrophages. In both lipopolysaccharide and cecal ligation and puncture induced acute lung injury mouse models, treatment with PV-K significantly reduced disease severity by alleviating pulmonary inflammation and inhibiting macrophage pyroptosis. Transcriptomic analysis revealed that PV-K enhanced SQSM1/p62-mediated autophagy through upregulation of the NRF2 signaling pathway. Mechanistically, PV-K facilitated the interaction between SQSTM1/p62 and NLRP3, promoting the autolysosomal degradation of NLRP3. Notably, the inhibitory effect of PV-K on macrophage pyroptosis during acute lung injury was abrogated in Nrf2 -/- mice. This study introduces a novel nanotherapeutic approach aiming at regulating macrophage pyroptosis by facilitating NLRP3 degradation, thereby controlling inflammation in ARDS/ALI. This strategy may complement existing clinical treatments for ARDS/ALI.https://doi.org/10.1186/s12951-025-03219-yNLRP3MacrophageNanoparticlesAutophagosomeALI/ARDS |
| spellingShingle | Yan Fan Jian Mei Yuehao Shen Ying Gao Lina Zhao Shuqi Meng Shuai Zhou Yu Qian Ying Zhang Zhiwei Wang Yu Song Jianfeng Liu Shuaijie Pei Yan Cui Hong Yang Shan-Yu Fung Keliang Xie Promotion of NLRP3 autophagosome degradation by PV-K nanodevice for protection against macrophage pyroptosis-mediated lung injury Journal of Nanobiotechnology NLRP3 Macrophage Nanoparticles Autophagosome ALI/ARDS |
| title | Promotion of NLRP3 autophagosome degradation by PV-K nanodevice for protection against macrophage pyroptosis-mediated lung injury |
| title_full | Promotion of NLRP3 autophagosome degradation by PV-K nanodevice for protection against macrophage pyroptosis-mediated lung injury |
| title_fullStr | Promotion of NLRP3 autophagosome degradation by PV-K nanodevice for protection against macrophage pyroptosis-mediated lung injury |
| title_full_unstemmed | Promotion of NLRP3 autophagosome degradation by PV-K nanodevice for protection against macrophage pyroptosis-mediated lung injury |
| title_short | Promotion of NLRP3 autophagosome degradation by PV-K nanodevice for protection against macrophage pyroptosis-mediated lung injury |
| title_sort | promotion of nlrp3 autophagosome degradation by pv k nanodevice for protection against macrophage pyroptosis mediated lung injury |
| topic | NLRP3 Macrophage Nanoparticles Autophagosome ALI/ARDS |
| url | https://doi.org/10.1186/s12951-025-03219-y |
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