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Species-agnostic polymeric formulations for inhalable messenger RNA delivery to the lung.
Rotolo, Laura; Vanover, Daryll; Bruno, Nicholas C; Peck, Hannah E; Zurla, Chiara; Murray, Jackelyn; Noel, Richard K; O'Farrell, Laura; Araínga, Mariluz; Orr-Burks, Nichole; Joo, Jae Yeon; Chaves, Lorena C S; Jung, Younghun; Beyersdorf, Jared; Gumber, Sanjeev; Guerrero-Ferreira, Ricardo; Cornejo, Santiago; Thoresen, Merrilee; Olivier, Alicia K; Kuo, Katie M; Gumbart, James C; Woolums, Amelia R; Villinger, Francois; Lafontaine, Eric R; Hogan, Robert J; Finn, M G; Santangelo, Philip J.
  • Rotolo L; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
  • Vanover D; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
  • Bruno NC; School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, USA.
  • Peck HE; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
  • Zurla C; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
  • Murray J; Department of Infectious Diseases, College of Veterinary Medicine University of Georgia, Athens, GA, USA.
  • Noel RK; Physiological Research Laboratory, Georgia Institute of Technology, Atlanta, GA, USA.
  • O'Farrell L; Physiological Research Laboratory, Georgia Institute of Technology, Atlanta, GA, USA.
  • Araínga M; New Iberia Research Center, University of Louisiana Lafayette, Lafayette, LA, USA.
  • Orr-Burks N; Department of Infectious Diseases, College of Veterinary Medicine University of Georgia, Athens, GA, USA.
  • Joo JY; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
  • Chaves LCS; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
  • Jung Y; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
  • Beyersdorf J; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
  • Gumber S; Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
  • Guerrero-Ferreira R; Robert P. Apkarian Integrated Electron Microscopy Core, Emory University, Atlanta, GA, USA.
  • Cornejo S; Department of Pathobiology and Population Medicine, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS, USA.
  • Thoresen M; Department of Pathobiology and Population Medicine, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS, USA.
  • Olivier AK; Department of Pathobiology and Population Medicine, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS, USA.
  • Kuo KM; School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, USA.
  • Gumbart JC; School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, USA.
  • Woolums AR; School of Physics, Georgia Institute of Technology, Atlanta, GA, USA.
  • Villinger F; Department of Pathobiology and Population Medicine, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS, USA.
  • Lafontaine ER; New Iberia Research Center, University of Louisiana Lafayette, Lafayette, LA, USA.
  • Hogan RJ; Department of Infectious Diseases, College of Veterinary Medicine University of Georgia, Athens, GA, USA.
  • Finn MG; Department of Infectious Diseases, College of Veterinary Medicine University of Georgia, Athens, GA, USA.
  • Santangelo PJ; Department of Veterinary Biosciences and Diagnostic Imaging, College of Veterinary Medicine University of Georgia, Athens, GA, USA.
Nat Mater ; 2022 Nov 28.
Article in English | MEDLINE | ID: covidwho-2278861
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-ß-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.
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Full text: Available Collection: International databases Database: MEDLINE Topics: Vaccines Language: English Journal subject: Science / Chemistry Year: 2022 Document Type: Article Affiliation country: S41563-022-01404-0

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Full text: Available Collection: International databases Database: MEDLINE Topics: Vaccines Language: English Journal subject: Science / Chemistry Year: 2022 Document Type: Article Affiliation country: S41563-022-01404-0