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Inhalable polymer nanoparticles for versatile mRNA delivery and mucosal vaccination

Suberi, A.; Grun, M. K.; Mao, T.; Goldman-Israelow, B.; Reschke, M.; Grundler, J.; Akhtar, L.; Lee, T.; Shin, K.; Piotrowski-Daspit, A. S.; Homer, R.; Iwasaki, A.; Suh, H. W.; Saltzman, W. M.

2022-03-23 bioengineering
10.1101/2022.03.22.485401 bioRxiv
Show abstract

An inhalable platform for mRNA therapeutics would enable minimally invasive and lung targeted delivery for a host of pulmonary diseases. Development of lung targeted mRNA therapeutics has been limited by poor transfection efficiency and risk of vehicle-induced pathology. Here we report an inhalable polymer-based vehicle for delivery of therapeutic mRNAs to the lung. We optimized biodegradable poly(amine-co-ester) polyplexes for mRNA delivery using end group modifications and polyethylene glycol. Our polyplexes achieved high transfection of mRNA throughout the lung, particularly in epithelial and antigen-presenting cells. We applied this technology to develop a mucosal vaccine for SARS-CoV-2. Intranasal vaccination with spike protein mRNA polyplexes induced potent cellular and humoral adaptive immunity and protected K18-hACE2 mice from lethal viral challenge. One-sentence summaryInhaled polymer nanoparticles (NPs) achieve high mRNA expression in the lung and induce protective immunity against SARS-CoV-2.

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