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信使核糖核酸-脂质纳米颗粒疫苗策略：佐剂对非实质肝细胞及耐受性的影响

mRNA-LNP vaccine strategies: Effects of adjuvants on non-parenchymal liver cells and tolerance.

作者信息

Svensson Malin, Limeres María José, Zeyn Yanira, Gambaro Rocio C, Islan German A, Berti Ignacio Rivero, Fraude-El Ghazi Silvia, Pretsch Leah, Hilbert Katja, Schneider Paul, Kaps Leonard, Bros Matthias, Gehring Stephan, Cacicedo Maximiliano L

机构信息

Children's Hospital, University Medical Center Mainz of the Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany.

Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany.

出版信息

Mol Ther Methods Clin Dev. 2025 Feb 4;33(1):101427. doi: 10.1016/j.omtm.2025.101427. eCollection 2025 Mar 13.

DOI:10.1016/j.omtm.2025.101427
PMID:40027262
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11872076/
Abstract

The liver, which plays pivotal roles in metabolism and immunity, often confers tolerance, suppressing immune responses to pathogens. Adjuvanted, lipid nanoparticle-encapsulated mRNA vaccines (mRNA-LNPs) offer a promising approach to overcome immune tolerance. In this study, the immunostimulatory activity of well-documented adjuvants, ., 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), resiquimod (R848), and polyinosinic:polycytidylic acid (Poly I:C), on non-parenchymal liver cells was determined. When co-applied with mRNA-loaded LNPs, these adjuvants enhanced immune responses at variable extents. Moreover, the efficiency of mRNA translation in the presence of cGAMP was comparable with the non-adjuvanted control. Repetitive co-application of adjuvants with mRNA-LNPs showed improvement in cellular responses when R848 or R848/cGAMP treatments were used. These findings emphasize the need to delineate the delicate balance between immunomodulatory properties and the efficiency of mRNA translation when selecting adjuvants for mRNA-LNP vaccines and offer insights on how to enhance immunity to infectious diseases and cancers that affect the liver.

摘要

肝脏在新陈代谢和免疫中发挥着关键作用，常常赋予耐受性，抑制对病原体的免疫反应。佐剂化的、脂质纳米颗粒包裹的mRNA疫苗（mRNA-LNP）为克服免疫耐受性提供了一种有前景的方法。在本研究中，测定了充分记录的佐剂，即2'3'-环鸟苷单磷酸-腺苷单磷酸（cGAMP）、瑞喹莫德（R848）和聚肌苷酸:聚胞苷酸（Poly I:C）对非实质肝细胞的免疫刺激活性。当与负载mRNA的LNP共同应用时，这些佐剂在不同程度上增强了免疫反应。此外，在cGAMP存在下mRNA翻译的效率与无佐剂对照相当。当使用R848或R848/cGAMP处理时，佐剂与mRNA-LNP的重复共同应用显示细胞反应有所改善。这些发现强调了在为mRNA-LNP疫苗选择佐剂时，需要明确免疫调节特性与mRNA翻译效率之间的微妙平衡，并为如何增强对影响肝脏的传染病和癌症的免疫力提供了见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dc3/11872076/5d5413ed3e1f/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dc3/11872076/925c3f028fa4/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dc3/11872076/b2dc25f542c9/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dc3/11872076/72060e7b1285/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dc3/11872076/fc225dd27cd2/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dc3/11872076/9642580aa811/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dc3/11872076/64f5fdd2b0aa/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dc3/11872076/5d5413ed3e1f/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dc3/11872076/925c3f028fa4/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dc3/11872076/b2dc25f542c9/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dc3/11872076/72060e7b1285/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dc3/11872076/fc225dd27cd2/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dc3/11872076/9642580aa811/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dc3/11872076/64f5fdd2b0aa/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7dc3/11872076/5d5413ed3e1f/gr6.jpg

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本文引用的文献

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Pharmaceutics. 2024 Jun 6;16(6):771. doi: 10.3390/pharmaceutics16060771.
2
Polymeric nanocapsules loaded with poly(I:C) and resiquimod to reprogram tumor-associated macrophages for the treatment of solid tumors.载有聚（I:C）和雷西莫韦的聚合物纳米胶囊，用于重编程肿瘤相关巨噬细胞以治疗实体瘤。
Front Immunol. 2024 Jan 8;14:1334800. doi: 10.3389/fimmu.2023.1334800. eCollection 2023.
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The advances of adjuvants in mRNA vaccines.
mRNA疫苗中佐剂的进展。
NPJ Vaccines. 2023 Oct 26;8(1):162. doi: 10.1038/s41541-023-00760-5.
4
Reducing cell intrinsic immunity to mRNA vaccine alters adaptive immune responses in mice.降低细胞对mRNA疫苗的固有免疫力会改变小鼠的适应性免疫反应。
Mol Ther Nucleic Acids. 2023 Oct 5;34:102045. doi: 10.1016/j.omtn.2023.102045. eCollection 2023 Dec 12.
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Immunogenicity of lipid nanoparticles and its impact on the efficacy of mRNA vaccines and therapeutics.脂质纳米颗粒的免疫原性及其对 mRNA 疫苗和治疗药物疗效的影响。
Exp Mol Med. 2023 Oct;55(10):2085-2096. doi: 10.1038/s12276-023-01086-x. Epub 2023 Oct 2.
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