title: A Single Methylene Group in Oligoalkylamine-Based Cationic Polymers and Lipids Promotes Enhanced mRNA Delivery.
abstract: The development of chemically modified mRNA holds great promise as a new class of biologic therapeutics. However, the intracellular delivery and endosomal escape of mRNA encapsulated in nanoparticles has not been systematically investigated. Here, we synthesized a diverse set of cationic polymers and lipids from a series of oligoalkylamines and subsequently characterized their mRNA delivery capability. Notably, a structure with an alternating alkyl chain length between amines showed the highest transfection efficiency, which was linked to a high buffering capacity in a narrow range of pH 6.2 to 6.5. Variation in only one methylene group resulted in enhanced mRNA delivery to both the murine liver as well as porcine lungs after systemic or aerosol administration, respectively. These findings reveal a novel fundamental structure-activity relationship for the delivery of mRNA that is independent of the class of mRNA carrier and define a promising new path of exploration in the field of mRNA therapeutics.
authors.affiliation: Department of Pediatrics, Ludwig Maximilians University, Lindwurmstrasse 2a, 80337, München, Germany.
authors.forename: Anita
authors.initials: A
authors.lastname: Jarzębińska
authors.affiliation: ethris GmbH, Semmelweisstrasse 3, 82152, Planegg, Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Pasewald
authors.affiliation: Institute of Molecular Immunology & Experimental Oncology, Technische Universität München, Ismaningerstrasse 22, 81675, München, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Lambrecht
authors.affiliation: Institute of Molecular Immunology & Experimental Oncology, Technische Universität München, Ismaningerstrasse 22, 81675, München, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Mykhaylyk
authors.affiliation: Institute of Molecular Immunology & Experimental Oncology, Technische Universität München, Ismaningerstrasse 22, 81675, München, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Kümmerling
authors.affiliation: ethris GmbH, Semmelweisstrasse 3, 82152, Planegg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Beck
authors.affiliation: ethris GmbH, Semmelweisstrasse 3, 82152, Planegg, Germany.
authors.forename: Günther
authors.initials: G
authors.lastname: Hasenpusch
authors.affiliation: ethris GmbH, Semmelweisstrasse 3, 82152, Planegg, Germany.|Department of Pediatrics, Ludwig Maximilians University, Lindwurmstrasse 2a, 80337, München, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Rudolph
authors.affiliation: ethris GmbH, Semmelweisstrasse 3, 82152, Planegg, Germany.|Institute of Molecular Immunology & Experimental Oncology, Technische Universität München, Ismaningerstrasse 22, 81675, München, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Plank
authors.affiliation: ethris GmbH, Semmelweisstrasse 3, 82152, Planegg, Germany. dohmen@ethris.com.
authors.forename: Christian
authors.identifier: 0000-0001-9711-7982
authors.initials: C
authors.lastname: Dohmen
mesh_terms: D000588:Amines / Q000737:chemistry*; D000818:Animals; D002412:Cations / Q000737:chemistry; D008055:Lipids / Q000737:chemistry*; D051379:Mice; D041681:NIH 3T3 Cells; D011108:Polymers / Q000737:chemistry*; D012333:RNA, Messenger / Q000235:genetics*; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D000588:Amines; D002412:Cations; D008055:Lipids; D011108:Polymers; D012333:RNA, Messenger
keywords: drug delivery; lipids; mRNA; polymers; transcript therapy