Regulating mRNA endosomal escape through lipid rafts: A review
Xinxin Wang1, Xin Shi2, Ruifeng Wang3
1College of Chemistry and Molecular Sciences, Henan University, Kaifeng, Henan 475004, China.
Abstract:
Messenger RNA (mRNA) therapeutics, enabled by lipid nanoparticles (LNPs) delivery systems, have revolutionized modern medicine by facilitating the delivery of genetic cargo to target cells. However, the efficient release of mRNA from LNPs within the endosomal pathways into the cytosol remains a major bottleneck in this field. Revisiting the formulation and function of mRNA-LNPs, it has been found that lipid rafts formed by cholesterol and distearoylphosphatidylcholine during the self-assembly process plan an essential role in the intracellular delivery and endosomal escape of mRNA-LNPs. These lipid rafts enhance the rigidity and stability of LNPs, facilitating mRNA encapsulation and closely contributing to improved intracellular delivery efficiency. By adjusting the composition or behavior of lipid rafts within LNPs-such as substituting cholesterol or altering the lipid phase-endosomal membranes can be destabilized, facilitating the escape of mRNA into the cytoplasm. This approach provides a promising strategy for rational design of mRNA delivery system and optimization of LNPs formulation. Additionally, methods for studying the mRNA escape process are summarized, as they serve as the foundation for achieving reliable and reproducible results.
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