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<p>Current mRNA-LNP systems face challenges in efficient co-delivery of nucleic acid adjuvants, limiting their capacity to elicit robust cellular immunity. To overcome the dissociation limitations of physically admixed CpG in conventional lipid nanoparticles, we developed a covalent conjugation platform that integrates TLR9 agonists with phospholipids via amide bonding. We synthesized a DSPE-CpG conjugate, which exhibited high loading efficiency (97.1%) onto mRNA-LNPs. The immune activation efficacy was evaluated in models encoding SARS-CoV-2 spike protein and HBV antigens. The DSPE-CpG-mRNA LNP system demonstrated enhanced cellular uptake via clathrin-mediated endocytosis, superior lymph node targeting of the adjuvant, and improved antigen expression in vivo. In the SARS-CoV-2 model, it induced high levels of IFN-γ⁺CD8⁺ T cells and elicited higher titers of specific IgG and neutralizing antibodies. In the HBV model, it significantly enhanced antigen-specific CD107a<sup>+</sup> and FasL<sup>+</sup> CTLs. Acute toxicity tests revealed no significant adverse effects. This covalent conjugation strategy, by ensuring co-localized delivery of antigen and adjuvant, provides an innovative and translatable platform for enhancing mRNA vaccine efficacy.</p> Graphical abstract <p></p>

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Covalent conjugation of TLR9 agonists to phospholipids enhances mRNA-LNP delivery efficiency and dendritic cell cross-priming

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月17日

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  • Wanting Ji,
  • Keer Zhu,
  • Yanyan Zhou,
  • Haomin Yan,
  • Jiani Wei,
  • Ying Zhu,
  • Sheng Li,
  • Yuqi Hong,
  • Jinyao Dai,
  • Shaohua Dong,
  • Haoyang Hu,
  • Jian You,
  • Yunqing Qiu,
  • Yan Lou

摘要

Current mRNA-LNP systems face challenges in efficient co-delivery of nucleic acid adjuvants, limiting their capacity to elicit robust cellular immunity. To overcome the dissociation limitations of physically admixed CpG in conventional lipid nanoparticles, we developed a covalent conjugation platform that integrates TLR9 agonists with phospholipids via amide bonding. We synthesized a DSPE-CpG conjugate, which exhibited high loading efficiency (97.1%) onto mRNA-LNPs. The immune activation efficacy was evaluated in models encoding SARS-CoV-2 spike protein and HBV antigens. The DSPE-CpG-mRNA LNP system demonstrated enhanced cellular uptake via clathrin-mediated endocytosis, superior lymph node targeting of the adjuvant, and improved antigen expression in vivo. In the SARS-CoV-2 model, it induced high levels of IFN-γ⁺CD8⁺ T cells and elicited higher titers of specific IgG and neutralizing antibodies. In the HBV model, it significantly enhanced antigen-specific CD107a+ and FasL+ CTLs. Acute toxicity tests revealed no significant adverse effects. This covalent conjugation strategy, by ensuring co-localized delivery of antigen and adjuvant, provides an innovative and translatable platform for enhancing mRNA vaccine efficacy.

Graphical abstract