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Harnessing Topology and Stereochemistry of Glycidylamine‐Derived Lipid Nanoparticles for in Vivo mRNA Delivery to Immune Cells in Spleen and Their Application for Cancer Vaccination

mRNA lipid nanoparticles (LNPs) have reached an inflection point and are now paving the way for a new wave of precision therapies. The design of nonhepatocyte RNA delivery systems without targeting ligands, however, remains a challenge. It is reported that the development of ligand‐free glycidylamin...

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Published in:Advanced functional materials 2023-11, Vol.33 (45), p.n/a
Main Authors: Abd Elwakil, Mahmoud M., Suzuki, Ryota, Khalifa, Alaa M., Elshami, Rania M., Isono, Takuya, Elewa, Yaser H.A., Sato, Yusuke, Nakamura, Takashi, Satoh, Toshifumi, Harashima, Hideyoshi
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Language:English
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Summary:mRNA lipid nanoparticles (LNPs) have reached an inflection point and are now paving the way for a new wave of precision therapies. The design of nonhepatocyte RNA delivery systems without targeting ligands, however, remains a challenge. It is reported that the development of ligand‐free glycidylamine (GA) derivatives containing LNPs (GA‐LNPs) that preferentially deliver mRNA to immune cells in the spleen. Notably, it is demonstrated that the stereochemistry of GA‐lipids has a significant impact on their self‐assembly and in vitro and in vivo RNA delivery efficiency and tropism. This impact is dependent on the monomeric structure of GA and number of stereogenic centers. Furthermore, the nonlinear topology of GA lipid derivatives induced a sevenfold improvement in mRNA delivery efficiency. The top‐performing estriol‐GA05‐30 LNPs elicited strong antitumor activity in a therapeutic and prophylactic cancer model and are well tolerated in mice. These results highlight the significance of the chemistry of ionizable lipids for extrahepatic RNA delivery and indicated a promising direction for the development of next‐generation mRNA immunotherapies. Nucleic acid therapeutics have the potential to revolutionize medicine and will pave the way for the development of a third generation of therapeutics. However, the safe and efficient intracellular delivery of nucleic acid is the key challenge for clinical translation. In the current study,  splenic antigen‐presenting cells are successfully reprogrammed in vivo via glycidylamine‐derived lipid nanoparticles to enable the next generation of mRNA cancer vaccines.
ISSN:1616-301X
1616-3028
DOI:10.1002/adfm.202303795