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<p>Lipid nanoparticles (LNPs) represent the leading delivery platform for mRNA vaccines with advantageous biocompatibility, scalability, adjuvant activity and often an acceptable safety profile. Here we investigate the physicochemical characteristics and adjuvanticity of four-component LNPs. Previous vaccine studies have demonstrated that altering the ionizable lipid influences the adjuvanticity of an LNP; however, the impact of the polyethylene glycol lipid and phospholipid has received less attention. Our mRNA–LNP vaccine formulations utilized different phospholipids and varying ratios of polyethylene glycol lipid, whereas the ionizable lipid and cholesterol remained approximately constant. We demonstrate that such modifications impact the magnitude and quality of the vaccine-elicited immune responses. We also dissect the underlying mechanisms and show that the biodistribution and cellular uptake of LNPs correlate with the magnitude and quality of the immune responses. These findings support the rational design of novel LNPs to tailor immune responses (cellular or humoral focused) based on the vaccine application.</p>

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Tailoring the adjuvanticity of lipid nanoparticles by PEG lipid ratio and phospholipid modifications

  • 期刊论文

  • 发表日期：

    2025年6月23日

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  • Máté Vadovics,
  • Wenchen Zhao,
  • Emily F. Daley,
  • Kieu Lam,
  • Owen Daly,
  • Khalid Rashid,
  • Hailey R. Lee,
  • Petra Schreiner,
  • Kendall A. Lundgreen,
  • Brian T. Gaudette,
  • Vladimir V. Shuvaev,
  • Evguenia Arguiri,
  • Hiromi Muramatsu,
  • András Sárközy,
  • Thandiswa Mdluli,
  • Junchao Xu,
  • Xuexiang Han,
  • Nina De Luna,
  • Diana Castaño,
  • Emily Bettini,
  • Edit Ábrahám,
  • Zoltan Lipinszki,
  • Giuseppe Carlucci,
  • Avinash Haridas Bansode,
  • Katelyn Nguyen,
  • Thuc M. Le,
  • Tony Luu,
  • Vladimir R. Muzykantov,
  • Paul Bates,
  • David Allman,
  • Michael J. Mitchell,
  • Michela Locci,
  • Caius G. Radu,
  • James Heyes,
  • Norbert Pardi

摘要

Lipid nanoparticles (LNPs) represent the leading delivery platform for mRNA vaccines with advantageous biocompatibility, scalability, adjuvant activity and often an acceptable safety profile. Here we investigate the physicochemical characteristics and adjuvanticity of four-component LNPs. Previous vaccine studies have demonstrated that altering the ionizable lipid influences the adjuvanticity of an LNP; however, the impact of the polyethylene glycol lipid and phospholipid has received less attention. Our mRNA–LNP vaccine formulations utilized different phospholipids and varying ratios of polyethylene glycol lipid, whereas the ionizable lipid and cholesterol remained approximately constant. We demonstrate that such modifications impact the magnitude and quality of the vaccine-elicited immune responses. We also dissect the underlying mechanisms and show that the biodistribution and cellular uptake of LNPs correlate with the magnitude and quality of the immune responses. These findings support the rational design of novel LNPs to tailor immune responses (cellular or humoral focused) based on the vaccine application.