Surface-Functionalized PEGylated Nanoparticles Deliver Messenger RNA to Pulmonary Immune Cells

Nanoparticles designed as messenger RNA (mRNA) carriers to deliver gene medicine have shown great potential to change the way lung disease states are managed. Controlling their delivery to the lung and the transgene expression in a specific population of cells remains a challenge. Here, we developed a series of nanoparticles with polyethylene glycol (PEG) corona prepared by condensing mRNA with PEG-grafted-polyethyleneimine (PEI-g-PEG) with different PEG terminal functional groups and grafting ratios. PEGylated nanoparticles (PEG grafting ratio was 0.5%) with amino or amino acid terminal groups showed the highest transgene expression levels in the lung following systemic administration, and cell profiling analysis indicated that pulmonary immune cells contributed to the majority of expression. We also showed that these nanoparticles can be prepared by the flash nanocomplexation method, which is a scalable and reproducible process, yielding lyophilizable nanoparticles that were stable for at least 4 months at −20 °C. These results suggest that these surface-functionalized PEGylated nanoparticles may serve as desirable carriers to deliver mRNA to the lung for pulmonary immunomodulation.