Yi Jing, Lu Yicheng, Liu Nan, Wang Zengming, Zhang Hui, Xing Haonan, Li Meng, Jin Lili, Zheng Aiping
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China; College of Pharmacy, Yanbian University, Yanji 133002, China.
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
J Control Release. 2025 Aug 10;384:113891. doi: 10.1016/j.jconrel.2025.113891. Epub 2025 May 27.
Mucosal vaccination plays a crucial role in activating frontline immune responses, preventing infection and transmission of respiratory pathogens. However, the development of effective mRNA mucosal vaccines faces multiple challenges, including mucosal barriers, suboptimal immune cell targeting, and limited induction of mucosal immunity. In this study, we develop a dual-functional mRNA-LNP-CS+Man vaccine by utilizing DMG-PEG2000-Chitosan and DMG-PEG2000-Mannose, capable of penetrating the pulmonary mucosal barrier and targeting immune cells in the lungs. The results show that, following intratracheal administration, mRNA-LNP-CS+Man exhibits prolonged retention in the lungs for up to 72 h, with widespread distribution across the entire lung and achieving high mRNA transfection throughout the lung, particularly in immune cells. After two immunizations, the vaccine induces strong systemic and mucosal immune responses compared to the unmodified LNP, including efficient production of IgG and IgG2a in serum, IgG and SIgA in bronchoalveolar lavage fluid, and Th1-type cytokines. Significant activation of lung germinal center B (GC B) cells and tissue-resident memory T (TRM) cells were observed, alongside the establishment of effective immune memory. The vaccine demonstrates strong protective efficacy against SARS-CoV-2 D614G pseudovirus in the lungs, offering a novel strategy for mRNA mucosal vaccine development.
黏膜疫苗接种在激活一线免疫反应、预防呼吸道病原体感染和传播方面发挥着关键作用。然而，有效的mRNA黏膜疫苗的开发面临多重挑战，包括黏膜屏障、免疫细胞靶向性欠佳以及黏膜免疫诱导有限。在本研究中，我们利用二肉豆蔻酰甘油-聚乙二醇2000-壳聚糖（DMG-PEG2000-Chitosan）和二肉豆蔻酰甘油-聚乙二醇2000-甘露糖（DMG-PEG2000-Mannose）开发了一种双功能mRNA-LNP-CS+Man疫苗，该疫苗能够穿透肺黏膜屏障并靶向肺部的免疫细胞。结果表明，经气管内给药后，mRNA-LNP-CS+Man在肺中保留时间延长，长达72小时，在整个肺中广泛分布，并在整个肺中实现高mRNA转染，尤其是在免疫细胞中。两次免疫后，与未修饰的LNP相比，该疫苗诱导了强烈的全身和黏膜免疫反应，包括血清中高效产生IgG和IgG2a、支气管肺泡灌洗液中产生IgG和SIgA以及Th1型细胞因子。观察到肺生发中心B（GC B）细胞和组织驻留记忆T（TRM）细胞显著活化，同时建立了有效的免疫记忆。该疫苗在肺中对SARS-CoV-2 D614G假病毒显示出强大的保护效力，为mRNA黏膜疫苗的开发提供了一种新策略。
