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<p>Ionizable lipids are critical determinants of lipid nanoparticle (LNP) performance for mRNA delivery, yet the influence of natural hydrophobic motifs in ionizable lipid on delivery efficiency and biosafety remains insufficiently explored. Here, we report a series of ionizable lipids incorporating cholesterol, dehydrocholesterol, vitamin D₃, or vitamin E as hydrophobic tails to systematically investigate how natural-molecule-derived structures regulate LNP behavior. The resulting mRNA-loaded LNPs exhibited nanoscale sizes from 150&#xa0;nm to 200&#xa0;nm, favorable apparent pKₐ values (6.4–6.9), and high mRNA encapsulation efficiencies (&gt; 90%). In vivo screening revealed that LNPs with ionizable lipids bearing two vitamin D₃-based tails achieved the highest luciferase expression following intramuscular administration, whereas the formulation bearing two rigid cholesterol-based tails showed reduced delivery efficiency, manifesting the importance of balancing hydrophobic-tail rigidity and flexibility for effective endosomal escape. Lead formulations demonstrated excellent colloidal stability, efficient cellular transfection, and low cytotoxicity. Importantly, compared with the benchmark SM-102-based LNP formulation, these natural-compound–derived LNPs significantly reduced muscle tissue damage, inflammatory cytokine release, and injection-associated pain in mice. This work establishes natural-compound-based ionizable lipids as a promising strategy to enhance both the efficacy and biosafety of mRNA delivery systems.</p> Graphical Abstract <p></p>

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Construction of Lipid Nanoparticles Based on Natural Molecules for Safe and Efficient mRNA Delivery

  • 期刊论文

  • 发表日期：

    2026年5月8日

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  • Taorui Zhong,
  • Haiyang Li,
  • Jiangsheng Xu,
  • Fang Zeng,
  • Shuizhu Wu

摘要

Ionizable lipids are critical determinants of lipid nanoparticle (LNP) performance for mRNA delivery, yet the influence of natural hydrophobic motifs in ionizable lipid on delivery efficiency and biosafety remains insufficiently explored. Here, we report a series of ionizable lipids incorporating cholesterol, dehydrocholesterol, vitamin D₃, or vitamin E as hydrophobic tails to systematically investigate how natural-molecule-derived structures regulate LNP behavior. The resulting mRNA-loaded LNPs exhibited nanoscale sizes from 150 nm to 200 nm, favorable apparent pKₐ values (6.4–6.9), and high mRNA encapsulation efficiencies (> 90%). In vivo screening revealed that LNPs with ionizable lipids bearing two vitamin D₃-based tails achieved the highest luciferase expression following intramuscular administration, whereas the formulation bearing two rigid cholesterol-based tails showed reduced delivery efficiency, manifesting the importance of balancing hydrophobic-tail rigidity and flexibility for effective endosomal escape. Lead formulations demonstrated excellent colloidal stability, efficient cellular transfection, and low cytotoxicity. Importantly, compared with the benchmark SM-102-based LNP formulation, these natural-compound–derived LNPs significantly reduced muscle tissue damage, inflammatory cytokine release, and injection-associated pain in mice. This work establishes natural-compound-based ionizable lipids as a promising strategy to enhance both the efficacy and biosafety of mRNA delivery systems.

Graphical Abstract