Exploring the role of cationic lipids in modulating immunogenicity and vaccine efficacy of mRNA-LNP--颗粒学报PARTICUOLOGY

Zhou, Y., Shan, X., Gu, R., Xia, Y., & Huang, X. (2025). Exploring the role of cationic lipids in modulating immunogenicity and vaccine efficacy of mRNA-LNP. Particuology, 97, 1-11. https://doi.org/10.1016/j.partic.2024.11.011

Exploring the role of cationic lipids in modulating immunogenicity and vaccine efficacy of mRNA-LNP

Yan Zhou^{a b c}, Xiangfei Shan^{a b c}, Renji Gu^a, Yufei Xia^{a b c *}, Xiaonan Huang^{a b c *}

a State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100081, China
b School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China
c Key Laboratory of Biopharmaceutical Preparation and Delivery, Chinese Academy of Sciences, Beijing, 10090, China

10.1016/j.partic.2024.11.011

Volume 97, February 2025, Pages 1-11

Received 22 October 2024, Revised 5 November 2024, Accepted 19 November 2024, Available online 5 December 2024, Version of Record 13 December 2024.

E-mail: yfxia@ipe.ac.cn; xnhuang@ipe.ac.cn

Highlights

• Cationic lipid incorporation into mRNA-LNP formulations modulates immunogenicity without requiring novel lipid design.

• The mRNA-LNPs with enhanced immunogenicity facilitate stronger DC activation and boost antitumor immune responses.

• Optimal cationic lipid content in mRNA-LNP formulations varies depending on ionizable lipid used.

• Enhanced immunogenicity of mRNA-LNPs may slightly reduce antigen-specific antibody response levels.

Abstract

The mRNA vaccines have become a transformative platform in medicine, with their success during the COVID-19 pandemic accelerating research in viral prevention and cancer therapy. Lipid nanoparticles (LNPs) enhance the stability and efficacy of mRNA vaccines, but achieving an optimal balance between innate immune activation and mRNA expression is crucial for their effectiveness. Classical cationic lipids, although largely replaced by ionizable lipids due to concerns over excessive immunogenicity, have demonstrated potential in cancer immunotherapy by inducing strong immune responses. In this study, we investigated whether incorporating cationic lipids into mRNA-LNP formulations could enhance immunogenicity without requiring new lipid designs. We introduced varying proportions of cationic lipids into D-Lin-MC3-DMA and SM-102-based LNPs and evaluated their impact on innate immune activation, along with long-term humoral and cellular immune responses. Our results showed that in MC3-based LNPs, cationic lipids significantly improved anti-tumor efficacy, though slightly diminished long-term humoral and cellular immunity. In contrast, in SM-102-based LNPs, cationic lipids enhanced anti-tumor effects without negatively impacting long-term immunity. These findings suggest that adding cationic lipid as an additional component allows for the fine-tuning of mRNA-LNP immunogenicity, expanding the potential applications of mRNA vaccines and simplifying LNP design.

Graphical abstract

Keywords

Lipid nanoparticle; mRNA vaccine; Immunogenicity; Cationic lipids; Immune response

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