Zeng, J.-Y., Lingesh, S., Krishnan, N. B., Loong, B. S. Y., Liu, M., Chen, Q., & Yang, Y. Y. (2025). Cholesterol‐Derived Mannosylated Polypeptide‐Formed Lipid Nanoparticles for Efficient in Vivo mRNA Delivery. Small Methods, 9(6). Portico. https://doi.org/10.1002/smtd.202401712
Abstract:
Effective delivery of lipid nanoparticles (LNPs)‐based mRNA vaccines to antigen presenting cells (APCs) is important for eliciting potent immune responses. However, most LNPs‐based mRNA vaccines usually suffer from insufficient accumulation in APCs due to the lack of active targeting capability, leading to the limited efficacy and the need for high injection dose. In this study, a series of cholesterol‐derived mannopolypeptide (CPSM) and cholesterol‐conjugated mannose (CM) derivatives is synthesized to prepare mannosylated LNPs for efficient mRNA delivery. The co‐assembly of CPSM and/or CM is demonstrated with ionizable lipid, helper lipid, and cholesterol into LNPs provides the colloidal stability of LNPs, and endows LNPs the ability to target APCs. The leading mannosylated LNPs including CPSM‐LNP and CM/CPSM‐LNP exhibit efficient mRNA transfection ability in dendritic cells and mice. Specifically, CPSM‐LNP and CM/CPSM‐LNP show preferential accumulation in the lymph nodes compared with commercial ALC‐LNP from Pfizer/BioNTech's COVID‐19 mRNA vaccine formulation. This study presents a straightforward yet effective strategy to synthesize cholesterol‐derived mannopolypeptides and prepare mannosylated LNPs for successful in vivo mRNA delivery.
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Publisher Copyright
Funding Info:
This research / project is supported by the Agency for Science, Technology and Research (A*STAR) - Industry Alignment Fund - Pre-positioning
Grant Reference no. : H22J1a0050
This research / project is supported by the National Research Foundation Singapore - Competitive Research Programme
Grant Reference no. : CRP27-2021-0038
Description:
This is the peer reviewed version of the following article: Zeng, J.-Y., Lingesh, S., Krishnan, N. B., Loong, B. S. Y., Liu, M., Chen, Q., & Yang, Y. Y. (2025). Cholesterol‐Derived Mannosylated Polypeptide‐Formed Lipid Nanoparticles for Efficient in Vivo mRNA Delivery. Small Methods, 9(6). Portico. https://doi.org/10.1002/smtd.202401712
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