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<p>Effective subunit vaccines against pathogen infection require potent adjuvant systems that can induce both humoral and cellular immune responses. Here, we present a nanoparticulate lipid adjuvant (NLA) platform based on ionizable lipid (IL) nanoparticles. A library of 124 structurally diverse ILs synthesized via Ugi four-component reaction (Ugi-4CR) is formulated with helper lipids into 124 nanoparticles, respectively. In vitro screening based on TNF-α production from splenocytes identifies a few NLA candidates with high performance. Furthermore, the formulations from the ILs with varied amine heads are checked for stimulating immune cells, including bone marrow-derived dendritic cells and RAW264.7 cells. The leading IL nanoparticles, NLAs, potently facilitate the immune activation by expressing TNF-α and costimulatory molecules, CD80 and CD86, respectively. When co-administered with RSV pre-F antigen in mice via intramuscular injection, the optimized formulation induces robust cellular and humoral immunity, with significantly enhanced central and effector memory T cell responses. Challenge studies against viral infection reveal that the leading formulation provides superior protection of mice with a comparable efficacy to AS01e-like liposome adjuvant. Safety evaluations, including hematology, blood biochemistry, and histopathological analyses, confirm a good biocompatibility. By using NLRP3 gene knockout cells, we confirm that the inflammatory properties of NLAs mainly rely on the NLRP3-based inflammasome pathway. This work demonstrates that the rationally designed IL-based NLAs can serve as high-performing yet accessible adjuvants to enhance the immunogenicity of subunit vaccines.</p>

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Nanoparticulate lipid adjuvants induce robust immunity against RSV infection

  • 期刊论文

  • 发表日期：

    2025年6月4日

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  • Yizi Zhou,
  • Zhan Gao,
  • Zepeng He,
  • Zhenfu Wen,
  • Zhihui Zhang,
  • Xuanli Jin,
  • Hong Liu,
  • Zhijia Liu,
  • Lixin Liu,
  • Yongming Chen

摘要

Effective subunit vaccines against pathogen infection require potent adjuvant systems that can induce both humoral and cellular immune responses. Here, we present a nanoparticulate lipid adjuvant (NLA) platform based on ionizable lipid (IL) nanoparticles. A library of 124 structurally diverse ILs synthesized via Ugi four-component reaction (Ugi-4CR) is formulated with helper lipids into 124 nanoparticles, respectively. In vitro screening based on TNF-α production from splenocytes identifies a few NLA candidates with high performance. Furthermore, the formulations from the ILs with varied amine heads are checked for stimulating immune cells, including bone marrow-derived dendritic cells and RAW264.7 cells. The leading IL nanoparticles, NLAs, potently facilitate the immune activation by expressing TNF-α and costimulatory molecules, CD80 and CD86, respectively. When co-administered with RSV pre-F antigen in mice via intramuscular injection, the optimized formulation induces robust cellular and humoral immunity, with significantly enhanced central and effector memory T cell responses. Challenge studies against viral infection reveal that the leading formulation provides superior protection of mice with a comparable efficacy to AS01e-like liposome adjuvant. Safety evaluations, including hematology, blood biochemistry, and histopathological analyses, confirm a good biocompatibility. By using NLRP3 gene knockout cells, we confirm that the inflammatory properties of NLAs mainly rely on the NLRP3-based inflammasome pathway. This work demonstrates that the rationally designed IL-based NLAs can serve as high-performing yet accessible adjuvants to enhance the immunogenicity of subunit vaccines.