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Nano Research 2024, 17(3): 1804-1817 https://doi.org/10.1007/s12274-023-6111-2
Research Article | Issue | Published: 08 September 2023

Natural long-chain saturated fatty acids doped LNPs enabling spleen selective mRNA translation and potent cancer immunotherapy

Show Author's Information Fazhan Wang1( ),  Meng Zhang1,  Meiling Tian2,  Jia Lou1,  Longze Pan1,  Xiaoke Gao1,  Lijing Zhang1,  Xiaohan Lou1,  Linyu Zhu1,  Yuqiao Sheng1,  Ming Wang1,  Rui Xue1,  Wenjing Deng3,  Shuai Shao2,  Zhihai Qin1,4( )
Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, China
Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, China
Department of Neuro-Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, China
Keywords:
cancer immunotherapy, mRNA vaccine, lipid nanoparticles, spleen, long-chain saturated fatty acid
Topics:
Biomaterials Gene therapy NanobiotechnologyTargeted drug deliveryVaccines
Cite this article:
Wang F, Zhang M, Tian M, et al. Natural long-chain saturated fatty acids doped LNPs enabling spleen selective mRNA translation and potent cancer immunotherapy. Nano Research, 2024, 17(3): 1804-1817. https://doi.org/10.1007/s12274-023-6111-2
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Abstract Full text Electronic supplementary material About this article

Rationally tailored lipid nanoparticles (LNPs) with efficient and tunable delivery of mRNA in vivo are crucial for mRNA vaccines. Selective expression of antigenic protein in lymphoid tissues/organs could improve the immunostimulatory efficacy and safety of LNPs-based mRNA vaccines. Inspired by the metabolic behavior that long-chain saturated fatty acids tending to enter lymphoid tissue rather than the liver, we developed fatty acid-doped LNPs capable of mediating differential protein expressions in the liver and spleen when administered intravenously. When the molar ratio of saturated fatty acid located 60%–70%, the doped LNPs achieved the spleen selective mRNA translation. The mechanism could be attributed to the different cellular uptake behaviors of saturated fatty acids in hepatocytes. Immunization with a model antigen (ovalbumin) mRNA-loaded spleen selective LNPs, we observed enhanced antigen-specific T cell immune responses, and potent immunotherapeutic and immunoprophylactic efficacy in the mouse lymphoma model. Our natural long-chain saturated fatty acids metabolic characteristics-inspired design of LNPs for spleen-selective mRNA vaccines delivery will provide references for designing mRNA vaccines with high efficacy and safety for tumor immunotherapy.


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Abstract
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Electronic supplementary material
About this article

Natural long-chain saturated fatty acids doped LNPs enabling spleen selective mRNA translation and potent cancer immunotherapy

Show Author's information Fazhan Wang1( ), Meng Zhang1, Meiling Tian2, Jia Lou1, Longze Pan1, Xiaoke Gao1, Lijing Zhang1, Xiaohan Lou1, Linyu Zhu1, Yuqiao Sheng1, Ming Wang1, Rui Xue1, Wenjing Deng3, Shuai Shao2, Zhihai Qin1,4( )
Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, China
Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, China
Department of Neuro-Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, China

Abstract

Rationally tailored lipid nanoparticles (LNPs) with efficient and tunable delivery of mRNA in vivo are crucial for mRNA vaccines. Selective expression of antigenic protein in lymphoid tissues/organs could improve the immunostimulatory efficacy and safety of LNPs-based mRNA vaccines. Inspired by the metabolic behavior that long-chain saturated fatty acids tending to enter lymphoid tissue rather than the liver, we developed fatty acid-doped LNPs capable of mediating differential protein expressions in the liver and spleen when administered intravenously. When the molar ratio of saturated fatty acid located 60%–70%, the doped LNPs achieved the spleen selective mRNA translation. The mechanism could be attributed to the different cellular uptake behaviors of saturated fatty acids in hepatocytes. Immunization with a model antigen (ovalbumin) mRNA-loaded spleen selective LNPs, we observed enhanced antigen-specific T cell immune responses, and potent immunotherapeutic and immunoprophylactic efficacy in the mouse lymphoma model. Our natural long-chain saturated fatty acids metabolic characteristics-inspired design of LNPs for spleen-selective mRNA vaccines delivery will provide references for designing mRNA vaccines with high efficacy and safety for tumor immunotherapy.

Keywords: cancer immunotherapy, mRNA vaccine, lipid nanoparticles, spleen, long-chain saturated fatty acid

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Publication history
Copyright
Acknowledgements

Publication history

Received: 05 July 2023
Revised: 18 August 2023
Accepted: 21 August 2023
Published: 08 September 2023
Issue date: March 2024

Copyright

© Tsinghua University Press 2023

Acknowledgements

Acknowledgements

This study was financial supported by the National Key Research and Development Program of China (No. 2021YFA1201102), Henan Medical Science and Technology Joint Building Program (No. SBGJ202102132), Henan Province Youth Talent Promoting Project (No. 2022HYTP047), the National Natural Science Foundation of China (Nos. 82003255, 82101385 and 82073231), Key Research and Development Project of Henan Province (No. 232102311224) and First-Class Clinical Medicine Discipline Construction Talents Cultivation Project of Zhengzhou University. Thanks are given to the Home for Researchers (https://www.home-for-researchers.com) for drawing the scheme.

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