Scholarlink

<p>Advanced functional lipid nanomaterials with precise structure-function relationships are pivotal to overcome extrahepatic delivery barriers in mRNA therapy. Here, we develop a chloroquine-inspired spleen-targeting system (CISTS) through rational molecular hybridization and combinatorial screening of quinoline-derived lipids. Computational simulations revealed enhanced mRNA binding via hydrogen bonding networks and TLR4/TLR7-targeting capacity inherent to chloroquine-mimetic headgroups. This molecular design enables CISTS to exhibit unique self-assembly behavior, as validated by cryo-EM and molecular dynamics, which promotes high-efficiency mRNA encapsulation and endosomal escape. Upon intravenous administration, CISTS achieves spleen-biased mRNA transfection while concurrently activating TLR-mediated immune pathways, conferring self-adjuvanting activity that drives potent Th1-biased responses. In murine melanoma models, CISTS-delivered ovalbumin mRNA elicited robust antigen-specific immunity, significantly suppressing tumor growth and extending survival. This work establishes a new paradigm of hybrid lipid nanomaterials that intrinsically integrates targeted delivery and immunostimulation, advancing next-generation mRNA vaccine design.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Chloroquine-inspired molecular hybrid lipids enable spleen-biased mRNA delivery with self-adjuvanting activity

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月21日

查看全文
  • Yue Li,
  • Binghao Guo,
  • Ruifeng Wang,
  • Jintao Hao,
  • Lu Huang,
  • Chaoxing He,
  • Meng Yan,
  • Kexin Cong,
  • Shaokun Yang,
  • Mengyang Liu,
  • Yanan Sun,
  • Han Song,
  • Huaxing Zhang,
  • Chenming Zhou,
  • Jinlong Qi,
  • Yupin Song,
  • Zhao Ma,
  • Defang Ouyang,
  • Lei Wang,
  • Bai Xiang

摘要

Advanced functional lipid nanomaterials with precise structure-function relationships are pivotal to overcome extrahepatic delivery barriers in mRNA therapy. Here, we develop a chloroquine-inspired spleen-targeting system (CISTS) through rational molecular hybridization and combinatorial screening of quinoline-derived lipids. Computational simulations revealed enhanced mRNA binding via hydrogen bonding networks and TLR4/TLR7-targeting capacity inherent to chloroquine-mimetic headgroups. This molecular design enables CISTS to exhibit unique self-assembly behavior, as validated by cryo-EM and molecular dynamics, which promotes high-efficiency mRNA encapsulation and endosomal escape. Upon intravenous administration, CISTS achieves spleen-biased mRNA transfection while concurrently activating TLR-mediated immune pathways, conferring self-adjuvanting activity that drives potent Th1-biased responses. In murine melanoma models, CISTS-delivered ovalbumin mRNA elicited robust antigen-specific immunity, significantly suppressing tumor growth and extending survival. This work establishes a new paradigm of hybrid lipid nanomaterials that intrinsically integrates targeted delivery and immunostimulation, advancing next-generation mRNA vaccine design.