Inhalable polymer nanoparticles for versatile mRNA delivery and mucosal vaccination

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.

Unadjuvanted intranasal spike vaccine elicits protective mucosal immunity against sarbecoviruses

“…By contrast, PACE materials have been developed to be relatively immunologically silent, enabling administration to locations more susceptible to immunopathology such as the respiratory tract. Chemically modifying PACE with polyethylene glycol dramatically improves in vivo lung delivery ( 32 ). To assess the utility of PACE encapsulating mRNA encoding spike protein as an IN booster, mRNA was extracted from BNT162b2 and encapsulated in PACE.…”

ISCOMs/MPLA‐Adjuvanted SDAD Protein Nanoparticles Induce Improved Mucosal Immune Responses and Cross‐Protection in Mice

“…[65] Although site-specific vaccination such as intranasal or pulmonary vaccination could increase the chances for antigen encounter and are more likely to elicit T RM and B RM in lungs, [65,66] ours and most emerging studies demonstrated that intradermal, intramuscular, and intranasal immunizations of mRNA vaccines could induce pulmonary resident memory T cells. [27,67,68] Therefore, the heterologous immunizations of systemic prime and mucosal boost will be another new way for nextgeneration mucosal vaccines. [69][70][71] In summary, we have developed a novel influenza SDAD protein nanoparticle vaccine and found that the ISCOMs/MPLA adjuvant combination could significantly enhance the immunogenicity and protective effectiveness induced by protein nanoparticles after intramuscular and intranasal immunizations.…”

Amphiphilic Block Copolymer Nanostructures as a Tunable Delivery Platform: Perspective and Framework for the Future Drug Product Development

“…Intranasal vaccination with PACE-mRNA conferred protection in a lethal viral challenge in K18-hACE2 mice. 165 Furthermore, Patel et al have used PBEA to develop mRNA formulations for nebulizer-assisted intranasal administration 166 while Rotolo et al also used PBEA-based formulations for intranasal delivery of mRNA, 167 demonstrating the translational potential of PNPs as mRNA carriers.…”

“…In the field of PNPs, Suberi et al have published their efforts to use biodegradable poly­(amine- co -ester) (PACE) polymers stabilized by poly­(ethylene glycol) (PEG) to encapsulate mRNA for SARS-CoV-2 spike protein and facilitate delivery to the lung epithelial cells without causing adverse inflammatory reactions. Intranasal vaccination with PACE-mRNA conferred protection in a lethal viral challenge in K18-hACE2 mice . Furthermore, Patel et al have used PBEA to develop mRNA formulations for nebulizer-assisted intranasal administration while Rotolo et al also used PBEA-based formulations for intranasal delivery of mRNA, demonstrating the translational potential of PNPs as mRNA carriers.…”