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Research Article

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

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
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We proposed a multisite complementary strategy that incorporates hydrophilic Mo and electrophilic V into Ni-based catalysts to divide the distinct steps on atomically dispersive sites and thus realize sequential regulation of the HER process. By management of reactive H2O molecules, the NiMoV oxides multisite catalysts surpass Pt/C hydrogen evolution activity (49 mV@10 mA∙cm−2 over 140 h).

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

mRNA vaccinelipid nanoparticlesspleenlong-chain saturated fatty acidcancer immunotherapy

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Nano Research
Volume 17 Issue 3,
March 2024
Pages 1804-1817
DOI: 10.1007/s12274-023-6111-2
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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