Li Man, Li You, Peng Ke, Wang Ying, Gong Tao, Zhang Zhirong, He Qin, Sun Xun
Key Laboratory of Drug Targeting, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China.
Key Laboratory of Drug Targeting, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China.
Acta Biomater. 2017 Dec;64:237-248. doi: 10.1016/j.actbio.2017.10.019. Epub 2017 Oct 10.
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.
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.
鼻内mRNA疫苗接种可提供针对大流行疾病的即时免疫保护。最近的研究表明，多种形式的聚乙烯亚胺（PEI）具有强大的粘膜佐剂活性，可显著促进鼻内mRNA疫苗的递送。然而，优化PEI的化学结构以最大化其佐剂活性并降低其毒性仍然是一个挑战。在这里，我们表明PEI的化学结构强烈影响PEI与mRNA的纳米复合物迁移到淋巴结并引发免疫反应的效果。将环糊精（CD）与PEI600或PEI2k共轭产生具有不同CD/PEI比率的CP（CD-PEI）聚合物。我们通过评估淋巴结迁移和免疫反应来分析CP600、CP2k和PEI25k作为鼻内mRNA疫苗载体的递送效果。在这些聚合物中，CP2k/mRNA在体外转染效率方面显著更高，在体内迁移到淋巴结并刺激树突状细胞成熟的能力更强，这进一步导致了强大的体液和细胞免疫反应，并且与PEI25k/mRNA相比，局部和全身毒性更低。这些结果证明了CD-PEI2k/mRNA纳米复合物作为一种高效转运至淋巴结的自佐剂疫苗递送载体的潜力。
当我们面临寨卡病毒等大流行疾病的爆发时，鼻内mRNA疫苗接种可针对高度变异的病毒提供即时大规模保护。各种基于聚合物的递送系统已成功应用于鼻内疫苗递送。然而，对于鼻内接种，聚合物载体的分子结构对淋巴结转运和树突状细胞成熟的影响很少被研究。因此，设计基于聚合物的疫苗递送系统并阐明分子结构与鼻内递送效率之间的关系对于最大化免疫反应至关重要。我们在此构建基于聚合物的自佐剂鼻内mRNA疫苗，以增强淋巴结转运并进一步改善免疫反应。
