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Abstract
Messenger RNA has now been used to vaccinate millions of people. However, the diversity of pulmonary pathologies, including infections, genetic disorders, asthma and others, reveals the lung as an important organ to directly target for future RNA therapeutics and preventatives. Here we report the screening of 166 polymeric nanoparticle formulations for functional delivery to the lungs, obtained from a combinatorial synthesis approach combined with a low-dead-volume nose-only inhalation system for mice. We identify P76, a poly-β-amino-thio-ester polymer, that exhibits increased expression over formulations lacking the thiol component, delivery to different animal species with varying RNA cargos and low toxicity. P76 allows for dose sparing when delivering an mRNA-expressed Cas13a-mediated treatment in a SARS-CoV-2 challenge model, resulting in similar efficacy to a 20-fold higher dose of a neutralizing antibody. Overall, the combinatorial synthesis approach allowed for the discovery of promising polymeric formulations for future RNA pharmaceutical development for the lungs.
Screening of hundreds of nanoparticle polymers identifies an effective and low-toxicity formulation for the functional delivery of RNA to the lungs of distinct animal species.
Details
; Gumber, Sanjeev 6 ; Guerrero-Ferreira, Ricardo 7 ; Cornejo, Santiago 8 ; Thoresen, Merrilee 8 ; Olivier, Alicia K. 8 ; Kuo, Katie M. 2 ; Gumbart, James C. 9
; Woolums, Amelia R. 8 ; Villinger, Francois 5
; Lafontaine, Eric R. 3 ; Hogan, Robert J. 10 ; Finn, M. G. 11
; Santangelo, Philip J. 1
1 Georgia Institute of Technology and Emory University, Wallace H. Coulter Department of Biomedical Engineering, Atlanta, USA (GRID:grid.213917.f) (ISNI:0000 0001 2097 4943)
2 Georgia Institute of Technology, School of Chemistry and Biochemistry, Atlanta, USA (GRID:grid.213917.f) (ISNI:0000 0001 2097 4943)
3 College of Veterinary Medicine University of Georgia, Department of Infectious Diseases, Athens, USA (GRID:grid.213876.9) (ISNI:0000 0004 1936 738X)
4 Georgia Institute of Technology, Physiological Research Laboratory, Atlanta, USA (GRID:grid.213917.f) (ISNI:0000 0001 2097 4943)
5 University of Louisiana Lafayette, New Iberia Research Center, Lafayette, USA (GRID:grid.266621.7) (ISNI:0000 0000 9831 5270)
6 Emory University, Yerkes National Primate Research Center, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502)
7 Emory University, Robert P. Apkarian Integrated Electron Microscopy Core, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502)
8 Mississippi State University, Department of Pathobiology and Population Medicine, College of Veterinary Medicine, Mississippi State, USA (GRID:grid.260120.7) (ISNI:0000 0001 0816 8287)
9 Georgia Institute of Technology, School of Chemistry and Biochemistry, Atlanta, USA (GRID:grid.213917.f) (ISNI:0000 0001 2097 4943); Georgia Institute of Technology, School of Physics, Atlanta, USA (GRID:grid.213917.f) (ISNI:0000 0001 2097 4943)
10 College of Veterinary Medicine University of Georgia, Department of Infectious Diseases, Athens, USA (GRID:grid.213876.9) (ISNI:0000 0004 1936 738X); College of Veterinary Medicine University of Georgia, Department of Veterinary Biosciences and Diagnostic Imaging, Athens, USA (GRID:grid.213876.9) (ISNI:0000 0004 1936 738X)
11 Georgia Institute of Technology, School of Chemistry and Biochemistry, Atlanta, USA (GRID:grid.213917.f) (ISNI:0000 0001 2097 4943); Georgia Institute of Technology, School of Biological Sciences, Atlanta, USA (GRID:grid.213917.f) (ISNI:0000 0001 2097 4943)