Lipopolyplex potentiates anti-tumor immunity of mRNA-based vaccination.
Lipopolyplex potentiates anti-tumor immunity of mRNA-based vaccination.
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DOI：
10.1016/j.biomaterials.2017.02.019
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发表时间：
2017-05
期刊：
影响因子：
14
通讯作者：
Shen H
中科院分区：
文献类型：
--
作者：
Persano S;Guevara ML;Li Z;Mai J;Ferrari M;Pompa PP;Shen H
基于 mRNA 的疫苗具有触发强大的抗癌免疫力的优点，而没有 DNA 疫苗基因组整合的潜在危险或肽疫苗抗原选择的限制。然而，由带正电荷的蛋白质核心结构中浓缩的mRNA分子组成的常规mRNA疫苗不能被抗原呈递细胞有效内化。它也无法为 mRNA 分子提供足够的保护，使其免受血浆和组织酶的降解。在这里，我们开发了一种脂多聚复合物 mRNA 疫苗，它由封装在载体中的聚（β-氨基酯）聚合物 mRNA 核心组成。 1,2-二油酰-sn-甘油-3-乙基磷酸胆碱/1,2-二油酰-sn-甘油-3-磷脂酰乙醇胺/1,2-二硬脂酰-sn-甘油-3-磷酸乙醇胺-N-[氨基(聚乙二醇)-2000 (EDOPC/DOPE/DSPE-PEG)脂质壳。这种核壳结构的 mRNA 疫苗通过巨胞饮作用进入树突状细胞。它通过 Toll 样受体 7/8 信号传导有效刺激树突状细胞中的干扰素-β 和白介素-12 表达，从而显示出内在的佐剂活性。用 mRNA 疫苗处理的树突状细胞表现出增强的抗原呈递能力。用脂多聚复合物mRNA治疗携带表达卵清蛋白抗原的肺转移性B16-OVA肿瘤的小鼠，观察到肿瘤结节减少了90%以上。总的来说，这种核壳结构为 mRNA 疫苗的开发提供了一个有前景的平台。
mRNA-based vaccines have the benefit of triggering robust anti-cancer immunity without the potential danger of genome integration from DNA vaccines or the limitation of antigen selection from peptide vaccines. Yet, a conventional mRNA vaccine comprising of condensed mRNA molecules in a positively charged protein core structure is not effectively internalized by the antigen-presenting cells. It cannot offer sufficient protection for mRNA molecules from degradation by plasma and tissue enzymes either. Here, we have developed a lipopolyplex mRNA vaccine that consists of a poly-(β-amino ester) polymer mRNA core encapsulated into a 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine/1,2-dioleoyl-sn-glycero-3-phosphatidyl-ethanolamine/1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000 (EDOPC/DOPE/DSPE-PEG) lipid shell. This core-shell structured mRNA vaccine enters dendritic cells through macropinocytosis. It displayed intrinsic adjuvant activity by potently stimulating interferon-β and interleukin-12 expression in dendritic cells through Toll-like receptor 7/8 signaling. Dendritic cells treated with the mRNA vaccine displayed enhanced antigen presentation capability. Mice bearing lung metastatic B16-OVA tumors expressing the ovalbumin antigen were treated with the lipopolyplex mRNA, and over 90% reduction of tumor nodules was observed. Collectively, this core-shell structure offers a promising platform for mRNA vaccine development.