Maniyamgama Nipuni, Bae Ki Hyun, Chang Zi Wei, Lee Jialing, Ang Melgious J Y, Tan Yong Jie, Ng Lisa F P, Renia Laurent, White Kevin P, Yang Yi Yan
Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, Centros #06-01, Singapore, 138668, Republic of Singapore.
A*STAR Infectious Diseases Labs (A*STAR ID Labs), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos #05-13, Singapore, 138648, Republic of Singapore.
Adv Sci (Weinh). 2025 Mar;12(11):e2407383. doi: 10.1002/advs.202407383. Epub 2025 Jan 30.
Intranasal delivery of mRNA vaccines offers promising opportunities to combat airborne viruses like SARS-CoV-2 by provoking mucosal immunity, which not only defends against respiratory infection but also prevents contagious transmission. However, the development of nasal mRNA vaccines has been hampered by the lack of effective means to overcome the mucus barrier. Herein, ionizable lipid-incorporated liquid lipid nanoparticles (iLLNs) capable of delivering mRNA cargo across airway mucosa are designed. Adjusting the ratios of ionizable and cationic lipids allows fine-tuning of the pK of iLLNs to the range of nasal mucosal pH (5.5-6.5), thus facilitating mucus penetration via the formation of near-neutral, PEGylated muco-inert surfaces. When nasally administered to mice, the top candidate iLLN-2/mRNA complexes enable about 60-fold greater reporter gene expression in the nasal cavity, compared to the benchmark mRNA-lipid nanoparticles (ALC-LNP) having the same lipid composition as that of BNT162b2 vaccine. Moreover, a prime-boost intranasal immunization of iLLN-2/mRNA complexes elicits a greater magnitude of SARS-CoV-2 spike-specific mucosal IgA and IgG response than ALC-LNP, without triggering any noticeable inflammatory reactions. Taken together, these results provide useful insights for the design of nasally deliverable mRNA formulations for prophylactic applications.
鼻内递送mRNA疫苗为对抗SARS-CoV-2等空气传播病毒提供了有前景的机会，可通过激发黏膜免疫来实现，这不仅能抵御呼吸道感染，还能防止传染性传播。然而，鼻用mRNA疫苗的开发受到缺乏有效手段克服黏液屏障的阻碍。在此，设计了能够将mRNA有效载荷递送至气道黏膜的可电离脂质掺入型液体脂质纳米颗粒（iLLNs）。调整可电离脂质和阳离子脂质的比例可将iLLNs的pK精细调节至鼻黏膜pH范围（5.5 - 6.5），从而通过形成近中性、聚乙二醇化的黏液惰性表面促进黏液渗透。当经鼻给予小鼠时，与具有与BNT162b2疫苗相同脂质组成的基准mRNA - 脂质纳米颗粒（ALC - LNP）相比，最佳候选iLLN - 2/mRNA复合物在鼻腔中的报告基因表达高出约60倍。此外，iLLN - 2/mRNA复合物的初免 - 加强鼻内免疫引发的SARS-CoV-2刺突特异性黏膜IgA和IgG反应比ALC - LNP更强，且未引发任何明显的炎症反应。综上所述，这些结果为设计用于预防性应用的鼻内递送mRNA制剂提供了有用的见解。
