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 summary Inhaled polymer nanoparticles (NPs) achieve high mRNA expression in the lung and induce protective immunity against SARS-CoV-2.
Competing Interest Statement
A.S.P., A.I., and W.M.S are cofounders of Xanadu Bio, and B.I. and T.M. serve as consultants for Xanadu Bio. A.I., B.I., and T.M. are listed as inventors on patent applications relating to intranasal spike-based SARS-CoV-2 vaccines filed by Yale University. A.I., W.M.S., B.I., T.M, A.S., M.H., A.S.P., and H.S. are listed as inventors on patent applications relating to intranasal PACE nanoparticle delivery-based vaccines filed by Yale University. A.S., M.K.G., and W.M.S are listed as inventors on patent applications relating to PACE-mRNA delivery to the lung filed by Yale University.
