Alexandra Suberi, Molly K Grun, Tianyang Mao, Benjamin Israelow, Melanie Reschke, Julian Grundler, Laiba Akhtar, Teresa Lee, Kwangsoo Shin, Alexandra S Piotrowski-Daspit, Robert J Homer, Akiko Iwasaki, Hee Won Suh, W Mark Saltzman
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Inhalable polymer nanoparticles for versatile mRNA delivery and mucosal vaccination.
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 summary: Inhaled polymer nanoparticles (NPs) achieve high mRNA expression in the lung and induce protective immunity against SARS-CoV-2.
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