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<p>Ionizable cationic lipids (ICLs) constitute the essential core of lipid nanoparticles (LNPs) for safe and efficacious mRNA therapeutics, their design evolving from empirical iterations to rational, modular paradigms that utilize molecular precision for organ-specific delivery. This review delineates advancements in synthetic methodologies, spanning traditional solution-phase routes alongside innovative solid-phase, biocatalytic, and machine learning-driven approaches. We further elucidate how nuanced structural engineering dictates organ-specific mRNA transduction, facilitating selective engagement of neural, pulmonary, splenic, lymphatic, skeletal, and pancreatic tissues. Addressing persistent hurdles in selectivity, formulation resilience, scalable manufacturing, and immune evasion, we propose forward-looking strategies for next-generation ICLs that synergize chemical sophistication with programmable bioactivity, poised to revolutionize precision gene medicine.</p>

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Research progress in ionizable cationic lipids in mRNA delivery: from synthetic strategies to applications

  • 期刊论文

  • 发表日期：

    2026年3月18日

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  • Xinwei Zhang,
  • Yuqin Liao,
  • Xuechuan Hong,
  • Yuling Xiao,
  • Xiaodong Zeng

摘要

Ionizable cationic lipids (ICLs) constitute the essential core of lipid nanoparticles (LNPs) for safe and efficacious mRNA therapeutics, their design evolving from empirical iterations to rational, modular paradigms that utilize molecular precision for organ-specific delivery. This review delineates advancements in synthetic methodologies, spanning traditional solution-phase routes alongside innovative solid-phase, biocatalytic, and machine learning-driven approaches. We further elucidate how nuanced structural engineering dictates organ-specific mRNA transduction, facilitating selective engagement of neural, pulmonary, splenic, lymphatic, skeletal, and pancreatic tissues. Addressing persistent hurdles in selectivity, formulation resilience, scalable manufacturing, and immune evasion, we propose forward-looking strategies for next-generation ICLs that synergize chemical sophistication with programmable bioactivity, poised to revolutionize precision gene medicine.