吸入型mRNAワクチンの新しい送達システムを開発(Advance in pulmonary mRNA vaccine development)

2026-01-13 ミュンヘン大学(LMU)

<関連情報>

• https://www.lmu.de/en/newsroom/news-overview/news/advance-in-pulmonary-mrna-vaccine-development-45dbcbe5.html
• https://www.sciencedirect.com/science/article/pii/S3050562325003022

肺mRNA送達のためのハイブリッドポリマーシステム:粘膜ワクチン開発の進展 A hybrid polymeric system for pulmonary mRNA delivery: Advancing mucosal vaccine development

Min Jiang, Felix Sieber-Schäfer, Simone P. Carneiro, Dana Matzek, Anny Nguyen, Diana Leidy Porras-Gonzalez, Arun Kumar Verma, Miriam Kolog-Gulko, David C. Jürgens, Gerald Burgstaller, Bastian Popper, Xun Sun, Olivia M. Merkel
Cell Biomaterials  Available online: 12 January 2026
DOI:https://doi.org/10.1016/j.celbio.2025.100311

Graphical abstract

Highlights

• PLGA/PBAE coordinates endosomal escape and timely mRNA release in APCs
• PLGA/PBAE enhances mRNA transfection in APCs and promotes immune activation
• PLGA/PBAE enables mucus penetration and effective mRNA transfection in airway models
• PLGA/PBAE retains transfection efficiency after nebulization

The bigger picture

Respiratory viruses, such as coronaviruses, influenza, and respiratory syncytial virus (RSV), continue to challenge global health, highlighting the need for vaccines that can elicit mucosal immunity directly in the airways. Pulmonary mRNA vaccination offers this promise, yet its development has been constrained by the difficulty of transporting mRNA across airway mucus and enabling efficient transfection in lung antigen-presenting cells through clinically relevant aerosol delivery.

In this study, we present a hybrid polymeric delivery system that leverages the complementary properties of poly(lactic-co-glycolic) acid (PLGA) and poly(β-amino esters) (PBAEs) to address these challenges. Designed to act through a coordinated sequence of mRNA protection, intracellular transport, and timely cytosolic release, the hybrid nanoparticles enable efficient mRNA transfection in antigen-presenting cells and support productive immune activation. Importantly, the hybrid nanoparticles can penetrate airway mucus, function in physiologically relevant human lung models, and withstand the mechanical stresses of vibrating-mesh nebulization, features essential for translating pulmonary mRNA delivery toward practical use. Such hybrid systems may help accelerate the development of next-generation inhalable vaccines and broaden the therapeutic reach of mRNA technologies.

Summary

Effective pulmonary messenger RNA (mRNA) vaccination requires delivery systems capable of overcoming the airway barrier and efficiently transfecting pulmonary antigen-presenting cells. Here, we developed a hybrid polymeric system incorporating poly(lactic-co-glycolic) acid (PLGA) and poly(β-amino esters) (PBAEs) to enhance pulmonary mRNA delivery. The components acted through a spatiotemporally coordinated cascade: early PLGA hydrolysis acidified endosomes, boosting PBAE protonation and tightening mRNA condensation for protection; increased buffering, driven by accelerated protonation, strengthened proton-sponge-mediated escape; and weakened electrostatic interactions in the cytosol enabled rapid mRNA release and translation in dendritic cells, supporting immune activation. These findings highlight the need to balance endosomal escape with timely mRNA release for functional expression. The system also overcame the mucus barrier and enabled mRNA transfection in ex vivo human lung tissue samples. After vibrating-mesh nebulization, it retained superior activity compared with lipid nanoparticles. These results support the PLGA/PBAE system as a viable platform for pulmonary mRNA vaccine delivery.