Structure-guided design of endosomolytic chloroquine-like lipid nanoparticles for mRNA delivery and genome editing
Abstract Despite remarkable progress in designing RNA delivery systems, endosomal escape remains a recognized challenge for efficient RNA delivery. In this study, we develop a robust mRNA delivery platform termed endosomolytic chloroquine-like optimized lipid nanoparticles (ecoLNPs) for versatile mR...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-05-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59501-y |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850277872446472192 |
|---|---|
| author | Zhen Liu Jiacai Wu Ning Wang Yongqi Lin Ruiteng Song Min Zhang Bin Li |
| author_facet | Zhen Liu Jiacai Wu Ning Wang Yongqi Lin Ruiteng Song Min Zhang Bin Li |
| author_sort | Zhen Liu |
| collection | DOAJ |
| description | Abstract Despite remarkable progress in designing RNA delivery systems, endosomal escape remains a recognized challenge for efficient RNA delivery. In this study, we develop a robust mRNA delivery platform termed endosomolytic chloroquine-like optimized lipid nanoparticles (ecoLNPs) for versatile mRNA delivery in vitro and in vivo via integrating the signature scaffold extracted from endosomolytic chloroquine into ionizable lipids. RNase-resistant ecoLNPs are capable of delivering a broad variety of mRNA payloads to diverse cell types, even hard-to-transfect 3D cells, with an efficiency of up to 18.9-fold higher than that of commercial transfection reagents. The pH-responsive endosomolytic activity of ecoLNPs can be largely attributed to the proton sponge effect and saposin B-promoted membrane disruption. In vivo, ecoLNPs enable potent local and systemic mRNA delivery and exhibit comparable potency to the clinically approved mRNA vaccine carrier, but strong tropism for lymph nodes following intramuscular injection. Furthermore, ecoLNPs are able to retain in vivo delivery potency for at least one week under non-frozen conditions and induce efficient genome editing in transgenic mice. Overall, the structure-guided integration strategy provides a pathway for de novo design of endosomolytic mRNA delivery systems. |
| format | Article |
| id | doaj-art-49d8bf826c40407d8b46b82baf3c80e0 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-49d8bf826c40407d8b46b82baf3c80e02025-08-20T01:49:43ZengNature PortfolioNature Communications2041-17232025-05-0116111510.1038/s41467-025-59501-yStructure-guided design of endosomolytic chloroquine-like lipid nanoparticles for mRNA delivery and genome editingZhen Liu0Jiacai Wu1Ning Wang2Yongqi Lin3Ruiteng Song4Min Zhang5Bin Li6Department of Infectious Disease, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan UniversitySchool of Medicine, Southern University of Science and TechnologySchool of Medicine, Southern University of Science and TechnologySchool of Medicine, Southern University of Science and TechnologyDepartment of Infectious Disease, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan UniversityDepartment of Ophthalmology, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan UniversityDepartment of Infectious Disease, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan UniversityAbstract Despite remarkable progress in designing RNA delivery systems, endosomal escape remains a recognized challenge for efficient RNA delivery. In this study, we develop a robust mRNA delivery platform termed endosomolytic chloroquine-like optimized lipid nanoparticles (ecoLNPs) for versatile mRNA delivery in vitro and in vivo via integrating the signature scaffold extracted from endosomolytic chloroquine into ionizable lipids. RNase-resistant ecoLNPs are capable of delivering a broad variety of mRNA payloads to diverse cell types, even hard-to-transfect 3D cells, with an efficiency of up to 18.9-fold higher than that of commercial transfection reagents. The pH-responsive endosomolytic activity of ecoLNPs can be largely attributed to the proton sponge effect and saposin B-promoted membrane disruption. In vivo, ecoLNPs enable potent local and systemic mRNA delivery and exhibit comparable potency to the clinically approved mRNA vaccine carrier, but strong tropism for lymph nodes following intramuscular injection. Furthermore, ecoLNPs are able to retain in vivo delivery potency for at least one week under non-frozen conditions and induce efficient genome editing in transgenic mice. Overall, the structure-guided integration strategy provides a pathway for de novo design of endosomolytic mRNA delivery systems.https://doi.org/10.1038/s41467-025-59501-y |
| spellingShingle | Zhen Liu Jiacai Wu Ning Wang Yongqi Lin Ruiteng Song Min Zhang Bin Li Structure-guided design of endosomolytic chloroquine-like lipid nanoparticles for mRNA delivery and genome editing Nature Communications |
| title | Structure-guided design of endosomolytic chloroquine-like lipid nanoparticles for mRNA delivery and genome editing |
| title_full | Structure-guided design of endosomolytic chloroquine-like lipid nanoparticles for mRNA delivery and genome editing |
| title_fullStr | Structure-guided design of endosomolytic chloroquine-like lipid nanoparticles for mRNA delivery and genome editing |
| title_full_unstemmed | Structure-guided design of endosomolytic chloroquine-like lipid nanoparticles for mRNA delivery and genome editing |
| title_short | Structure-guided design of endosomolytic chloroquine-like lipid nanoparticles for mRNA delivery and genome editing |
| title_sort | structure guided design of endosomolytic chloroquine like lipid nanoparticles for mrna delivery and genome editing |
| url | https://doi.org/10.1038/s41467-025-59501-y |
| work_keys_str_mv | AT zhenliu structureguideddesignofendosomolyticchloroquinelikelipidnanoparticlesformrnadeliveryandgenomeediting AT jiacaiwu structureguideddesignofendosomolyticchloroquinelikelipidnanoparticlesformrnadeliveryandgenomeediting AT ningwang structureguideddesignofendosomolyticchloroquinelikelipidnanoparticlesformrnadeliveryandgenomeediting AT yongqilin structureguideddesignofendosomolyticchloroquinelikelipidnanoparticlesformrnadeliveryandgenomeediting AT ruitengsong structureguideddesignofendosomolyticchloroquinelikelipidnanoparticlesformrnadeliveryandgenomeediting AT minzhang structureguideddesignofendosomolyticchloroquinelikelipidnanoparticlesformrnadeliveryandgenomeediting AT binli structureguideddesignofendosomolyticchloroquinelikelipidnanoparticlesformrnadeliveryandgenomeediting |