Modular Supramolecular Polycations Enable Efficient Delivery of Diverse RNA Therapeutics and Vaccines
Abstract
ABSTRACT We describe a modular, diverse, and customizable supramolecular‐materials platform that can deliver nucleic acids in vitro and in vivo. The chemistries deployed enable the generation of multiple supramolecular polycations, which can associate with RNA to form polyelectrolyte complexes, but which have the unique feature of reversible cross‐links, via host–guest interactions of monomers that display aromatic amino acid termini with cucurbit[8]uril (CB[8]). Families of supramolecular polymers can be prepared by simple variation in monomer structure, enabling the tuning of properties. We demonstrate that these supramolecular polyelectrolyte complexes with RNA can be prepared easily via automatable procedures to generate nanoparticles that meet Critical Quality Attributes for manufactured RNA vaccines and therapeutics. We show that these materials can deliver RNA to a range of cell types, displaying reporter‐protein expression at levels equivalent to, or greater than, commercial transfection reagents, with no acute adverse phenotypic effects. Finally, we demonstrate the success of our materials platform across a range of nucleic acid types, with expression of mRNA within tumors of an orthotopic Triple‐Negative Breast Cancer mouse model, knockdown of a kinase implicated in cancer progression via siRNA, and effective protection against H1N1 influenza virus challenge in mice following injections of self‐amplifying RNA.
Article Details
Authors (27)
Rafał Jerzy Kopiasz
School of Pharmacy University of Nottingham Nottingham UK
Hadijatou J. Sallah
Department of Infectious Disease South Kensington Campus Imperial College London London UK
Robert J. Cavanagh
School of Pharmacy University of Nottingham Nottingham UK
Sal Jones
School of Pharmacy University of Nottingham Nottingham UK
Cara Moloney
School of Pharmacy University of Nottingham Nottingham UK
Lewis O'Shaughnessy
School of Pharmacy University of Nottingham Nottingham UK
Phoebe McCrorie
Biodiscovery Institute School of Medicine University of Nottingham Nottingham UK
Ala’ Salem
Aqdot Ltd Cambridge UK
Hulya Bayraktutan
School of Pharmacy University of Nottingham Nottingham UK
Aimée S. Jeluk
School of Pharmacy University of Nottingham Nottingham UK
Luke A. Granger
Department of Infectious Disease South Kensington Campus Imperial College London London UK
Francois Hallac
Department of Engineering, Faculty of Natural, Mathematical and Engineering Sciences King's College London The Strand London UK
Alison A. Ritchie
Biodiscovery Institute School of Medicine University of Nottingham Nottingham UK
Shreeya Parmar
Biodiscovery Institute School of Medicine University of Nottingham Nottingham UK
Anna M. Grabowska
Biodiscovery Institute School of Medicine University of Nottingham Nottingham UK
Poulam Patel
Biodiscovery Institute School of Medicine University of Nottingham Nottingham UK
Srinivasan Madhusudan
Ruman Rahman
Alan McIntyre
Biodiscovery Institute School of Medicine University of Nottingham Nottingham UK
Robin J. Shattock
Charalampos Makatsoris
Department of Engineering, Faculty of Natural, Mathematical and Engineering Sciences King's College London The Strand London UK
Roger Coulston
Aqdot Ltd Cambridge UK
Andrew M. Howe
Aqdot Ltd Cambridge UK
Pratik Gurnani
UCL School of Pharmacy University College London London UK
Snjezana Stolnik
School of Pharmacy University of Nottingham Nottingham UK
John S. Tregoning
Cameron Alexander
School of Pharmacy University of Nottingham Nottingham UK