Midoux Patrick, Pichon Chantal
Centre de Biophysique Moléculaire, CNRS UPR4301, Inserm and Université d'Orléans, Orléans, 45071, cedex 02, France.
Expert Rev Vaccines. 2015 Feb;14(2):221-34. doi: 10.1586/14760584.2015.986104. Epub 2014 Dec 26.
Synthetic mRNAs can become biopharmaceutics allowing vaccination against cancer, bacterial and virus infections. Clinical trials with direct administration of synthetic mRNAs encoding tumor antigens demonstrated safety and induction of tumor-specific immune responses. Although immune responses are generated by naked mRNAs, their formulations with chemical carriers are expected to provide more specificity and internalization in dendritic cells (DCs) for better immune responses and dose reduction. This review reports lipid-based formulations (LBFs) that have proved preclinical efficacy. The selective delivery of mRNA LBFs to favor intracellular accumulation in DCs and reduction of the effective doses is discussed, notably to decorate LBFs with carbohydrates or glycomimetics allowing endocytosis in DCs. We also report how smart intracellular delivery is achieved using pH-sensitive lipids or polymers for an efficient mRNA escape from endosomes and limitations regarding cytosolic mRNA location for translation.
合成mRNA可成为生物制药，用于癌症、细菌和病毒感染的疫苗接种。直接施用编码肿瘤抗原的合成mRNA的临床试验证明了其安全性以及诱导肿瘤特异性免疫反应的能力。尽管裸mRNA可产生免疫反应，但预计其与化学载体的配方能在树突状细胞（DC）中提供更高的特异性和内化作用，从而产生更好的免疫反应并减少剂量。本综述报道了已证明具有临床前疗效的基于脂质的配方（LBF）。讨论了mRNA LBF的选择性递送，以促进其在DC中的细胞内积累并降低有效剂量，特别是通过用碳水化合物或糖模拟物修饰LBF，使其能够在DC中进行内吞作用。我们还报告了如何使用pH敏感脂质或聚合物实现智能细胞内递送，以促进mRNA从内体有效逃逸，以及关于胞质mRNA翻译位置的局限性。
