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Lipid tail heterogeneity enables organ-selective mRNA delivery for in vivo CRISPR-Cas9 gene editing
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DOI：10.1016/j.mattod.2026.103373.png)
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Abstract
En 中文
The precise delivery of mRNA to extrahepatic tissues remains a formidable bottleneck in the clinical translation of mRNA-based therapeutics. Conventional strategies for engineering organ-tropic lipid nanoparticles (LNPs) have predominantly focused on the chemical modification of ionizable lipid headgroups or linkers. However, this narrow focus often limits the diversity of achievable targeting profiles and fails to exploit the full structural potential of the lipid scaffold. Here, we introduce heterogeneous tail (HETAIL) LNPs, a platform developed through the rational engineering of lipid tail diversity to break these limitations. By systematically modulating the saturation, length, and branching of the lipid tails, we successfully engineered a library of LNPs capable of highly selective mRNA delivery to a broad spectrum of tissues, including the liver, lungs, spleen, lymph nodes, and bone marrow. Our mechanistic investigations demonstrate that tail heterogeneity dictates organ selectivity by fine-tuning the lipid pKa and orchestrating the formation of distinct protein coronas upon systemic administration. Furthermore, molecular dynamics simulations reveal that tail diversity fundamentally alters membrane microstructure and thermodynamic energetics, leading to unique interfacial behaviors that govern cellular uptake. Finally, HETAIL LNPs achieve organ-selective CRISPR/Cas9-mediated genome editing in vivo, showing great therapeutic potential of the platform.
Keywords:
Lipid nanoparticles
Heterogeneous tails
Organ-selective mRNA delivery
Protein corona
CRISPR-Cas9 gene editing
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