中文摘要：本研究表明，聚乙烯亚胺（PEI）的化学结构能够显著影响PEI纳米化合物的稳定性及mRNA往淋巴结的迁移能力，提高免疫反应。试验将环式糊精与PEI600或PEI2k按照不同比例组合，形成CP (CD-PEI)聚合物，通过评价淋巴结的运动情况和免疫反应分析CP600、CP2k和PEI25k作为mRNA疫苗载体的传递效率。结果表明，CP2k/mRNA多聚体体外转染效率更高，迁移到淋巴结的能力更强，体外更能刺激树突状细胞成熟，从而诱导产生体液免疫和细胞免疫，且PEI25k/mRNA的毒性更低。该研究结果表明PEI2k/mRNA纳米复合物具有自我传递和佐剂功效，能够更加有效地促进疫苗向淋巴结迁移。
 
外文摘要：Intranasal mRNA vaccination provides immediate immune protection against pandemic diseases. Recent studies have shown that diverse forms of polyethyleneimine (PEI) have potent mucosal adjuvant activity, which could significantly facilitate the delivery of intranasal mRNA vaccines. Nevertheless, optimizing the chemical structure of PEI to maximize its adjuvanticity and decrease its toxicity remains a challenge. Here we show that the chemical structure of PEI strongly influences how well nanocomplexes of PEI and mRNA migrate to the lymph nodes and elicit immune responses. Conjugating cyclodextrin (CD) with PEI600 or PEI2k yielded CP (CD-PEI) polymers with different CD/PEI ratios. We analyzed the delivery efficacy of CP600, CP2k, and PEI25k as intranasal mRNA vaccine carriers by evaluating the lymph nodes migration and immune responses. Among these polymers, CP2k/mRNA showed significantly higher in vitro transfection efficiency, stronger abilities to migrate to lymph nodes and stimulate dendritic cells maturation in vivo, which further led to potent humoral and cellular immune responses, and showed lower local and systemic toxicity than PEI25k/mRNA. These results demonstrate the potential of CD-PEI2k/mRNA nanocomplex as a self-adjuvanting vaccine delivery vehicle that traffics to lymph nodes with high efficiency. Statement of Significance As we face outbreaks of pandemic diseases such as Zika virus, intranasal mRNA vaccination provides instant massive protection against highly variant viruses. Various polymer-based delivery systems have been successfully applied in intranasal vaccine delivery. However, the influence of molecular structure of the polymeric carriers on the lymph node trafficking and dendritic cell maturation is seldom studied for intranasal vaccination. Therefore, engineering polymer-based vaccine delivery system and elucidating the relationship between molecular structure and the intranasal delivery efficiency are essential for maximizing the immune responses. We hereby construct self-adjuvanting polymer-based intranasal mRNA vaccines to enhance lymph node trafficking and further improve immune responses.
外文关键词： mRNA vaccine, CD-PEI, Lymph node migration, Intranasal, Adjuvant activity
作者：Li, M; Li, Y; Peng, K; Wang, Y; Gong, T; Zhang, ZR; He, Q; Sun, X
作者单位：四川大学
期刊名称：ACTA BIOMATERIALIA
期刊影响因子：6.66
出版年份：2017
出版刊次：12
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