Trehalose-loaded LNPs enhance mRNA stability and bridge in vitro in vivo efficacy gap
Abstract Lyophilization enhances mRNA vaccine stability, but conventional approaches using external trehalose for lipid nanoparticle (LNP) colloidal stability neglect mRNA chemical degradation and are compromised in vivo efficacy. Here, we report a dual-function trehalose strategy integrating its ex...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-08-01
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| Series: | npj Vaccines |
| Online Access: | https://doi.org/10.1038/s41541-025-01253-3 |
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| author | Xu-Han Liu Hui-Ping Song Ling-Ling Tao Zhe Zhai Jin-Xing Huang Yong-Xian Cheng |
| author_facet | Xu-Han Liu Hui-Ping Song Ling-Ling Tao Zhe Zhai Jin-Xing Huang Yong-Xian Cheng |
| author_sort | Xu-Han Liu |
| collection | DOAJ |
| description | Abstract Lyophilization enhances mRNA vaccine stability, but conventional approaches using external trehalose for lipid nanoparticle (LNP) colloidal stability neglect mRNA chemical degradation and are compromised in vivo efficacy. Here, we report a dual-function trehalose strategy integrating its external and internal roles within LNP. This strategy enables trehalose to externally form a vitrified matrix that preserves LNP colloidal integrity, while internally stabilizing mRNA through hydrogen bonding, markedly reducing chemical degradation during storage compared to LNP relying solely on externally added trehalose. Crucially, co-loaded trehalose is co-delivered into cells, bridging the in vitro-in vivo gap by mitigating oxidative stress through reduced reactive oxygen species (ROS) and malondialdehyde (MDA) alongside elevated glutathione (GSH) and superoxide dismutase (SOD). This is corroborated by downregulated cytoplasmic and nuclear nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Our strategy provides a simple, universally adaptable, and scalable method to enhance mRNA-LNP formulations stability without exogenous components or complex lyophilization steps. |
| format | Article |
| id | doaj-art-3a1e2a9feb6f497d95784d3a2c438ac7 |
| institution | Kabale University |
| issn | 2059-0105 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Vaccines |
| spelling | doaj-art-3a1e2a9feb6f497d95784d3a2c438ac72025-08-24T11:06:35ZengNature Portfolionpj Vaccines2059-01052025-08-0110111210.1038/s41541-025-01253-3Trehalose-loaded LNPs enhance mRNA stability and bridge in vitro in vivo efficacy gapXu-Han Liu0Hui-Ping Song1Ling-Ling Tao2Zhe Zhai3Jin-Xing Huang4Yong-Xian Cheng5Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Shenzhen UniversityDepartment of Traditional Chinese Medicine, Qingdao Central Hospital, University of Health and Rehabilitation SciencesGuangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Shenzhen UniversityGuangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Shenzhen UniversityGuangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Shenzhen UniversityGuangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Shenzhen UniversityAbstract Lyophilization enhances mRNA vaccine stability, but conventional approaches using external trehalose for lipid nanoparticle (LNP) colloidal stability neglect mRNA chemical degradation and are compromised in vivo efficacy. Here, we report a dual-function trehalose strategy integrating its external and internal roles within LNP. This strategy enables trehalose to externally form a vitrified matrix that preserves LNP colloidal integrity, while internally stabilizing mRNA through hydrogen bonding, markedly reducing chemical degradation during storage compared to LNP relying solely on externally added trehalose. Crucially, co-loaded trehalose is co-delivered into cells, bridging the in vitro-in vivo gap by mitigating oxidative stress through reduced reactive oxygen species (ROS) and malondialdehyde (MDA) alongside elevated glutathione (GSH) and superoxide dismutase (SOD). This is corroborated by downregulated cytoplasmic and nuclear nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Our strategy provides a simple, universally adaptable, and scalable method to enhance mRNA-LNP formulations stability without exogenous components or complex lyophilization steps.https://doi.org/10.1038/s41541-025-01253-3 |
| spellingShingle | Xu-Han Liu Hui-Ping Song Ling-Ling Tao Zhe Zhai Jin-Xing Huang Yong-Xian Cheng Trehalose-loaded LNPs enhance mRNA stability and bridge in vitro in vivo efficacy gap npj Vaccines |
| title | Trehalose-loaded LNPs enhance mRNA stability and bridge in vitro in vivo efficacy gap |
| title_full | Trehalose-loaded LNPs enhance mRNA stability and bridge in vitro in vivo efficacy gap |
| title_fullStr | Trehalose-loaded LNPs enhance mRNA stability and bridge in vitro in vivo efficacy gap |
| title_full_unstemmed | Trehalose-loaded LNPs enhance mRNA stability and bridge in vitro in vivo efficacy gap |
| title_short | Trehalose-loaded LNPs enhance mRNA stability and bridge in vitro in vivo efficacy gap |
| title_sort | trehalose loaded lnps enhance mrna stability and bridge in vitro in vivo efficacy gap |
| url | https://doi.org/10.1038/s41541-025-01253-3 |
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