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Comb-structured mRNA vaccine tethered with short double-stranded RNA adjuvants maximizes cellular immunity for cancer treatment
bioRxiv - Bioengineering Pub Date : 2022-08-20 , DOI: 10.1101/2022.01.18.476829
Theofilus A Tockary , Saed Abbasi , Miki Masai , Naoto Yoshinaga , Shigeto Fukushima , Kazunori Kataoka , Satoshi Uchida

Integrating antigen-encoding mRNA and immunostimulatory adjuvant into a single formulation is a promising approach to potentiating the efficacy of mRNA vaccines. Here, we developed a scheme based on RNA engineering to integrate adjuvancy directly into antigen-encoding mRNA strands without hampering the ability to express antigen proteins. Short double-stranded RNA (dsRNA) was designed to target retinoic acid-inducible gene-I (RIG-I), an innate immune receptor, for effective cancer vaccination and then tethered onto mRNA strand via hybridization. Tuning the dsRNA structure and microenvironment by changing its length and sequence enabled the determination of the structure of dsRNA-tethered mRNA efficiently stimulating RIG-I. Eventually, the formulation loaded with dsRNA-tethered mRNA of the optimal structure effectively activated mouse and human dendritic cells and drove them to secrete a broad spectrum of proinflammatory cytokines without increasing the secretion of anti-inflammatory cytokines. Notably, the immunostimulating intensity was tunable by modulating the number of dsRNA along mRNA strand, which prevents excessive immunostimulation. Versatility in the applicable formulation is a practical advantage of the dsRNA-tethered mRNA. Its formulation with three existing systems, i.e., anionic lipoplex, ionizable lipid-based lipid nanoparticles, and polyplex micelles, induced appreciable cellular immunity in the mice model. Of particular interest, dsRNA-tethered mRNA encoding ovalbumin (OVA) formulated in anionic lipoplex used in clinical trials exerted a significant therapeutic effect in the mouse lymphoma (E.G7-OVA) model. In conclusion, the system developed here provides a simple and robust platform to supply the desired intensity of immunostimulation in various formulations of mRNA cancer vaccines.

中文翻译:

与短双链 RNA 佐剂结合的梳状结构 mRNA 疫苗可最大限度地提高癌症治疗的细胞免疫

将编码抗原的 mRNA 和免疫刺激佐剂整合到单一制剂中是增强 mRNA 疫苗功效的一种有前途的方法。在这里,我们开发了一种基于 RNA 工程的方案,将佐剂直接整合到编码抗原的 mRNA 链中,而不妨碍表达抗原蛋白的能力。短双链 RNA (dsRNA) 旨在靶向视黄酸诱导基因-I (RIG-I),一种先天免疫受体,用于有效的癌症疫苗接种,然后通过杂交连接到 mRNA 链上。通过改变 dsRNA 的长度和序列来调整 dsRNA 结构和微环境,可以确定 dsRNA-tethered mRNA 的结构,从而有效地刺激 RIG-I。最终,装载了具有最佳结构的 dsRNA 束缚 mRNA 的制剂有效地激活了小鼠和人类树突状细胞,并促使它们分泌广谱的促炎细胞因子,而不会增加抗炎细胞因子的分泌。值得注意的是,免疫刺激强度可通过调节沿 mRNA 链的 dsRNA 数量来调节,从而防止过度免疫刺激。适用配方的多功能性是 dsRNA-tethered mRNA 的实际优势。其配方与三个现有系统,适用配方的多功能性是 dsRNA-tethered mRNA 的实际优势。其配方与三个现有系统,适用配方的多功能性是 dsRNA-tethered mRNA 的实际优势。其配方与三个现有系统,例如,阴离子脂质复合物、可电离的基于脂质的脂质纳米颗粒和复合胶束在小鼠模型中诱导了明显的细胞免疫。特别令人感兴趣的是,在临床试验中使用的阴离子脂质复合物中配制的 dsRNA-tethered mRNA 编码卵清蛋白 (OVA) 在小鼠淋巴瘤 (E.G7-OVA) 模型中发挥了显着的治疗效果。总之,这里开发的系统提供了一个简单而强大的平台,可以在各种 mRNA 癌症疫苗制剂中提供所需的免疫刺激强度。
更新日期:2022-08-23
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