Selective Replacement of Cholesterol with Cationic Amphiphilic Drugs Enables the Design of Lipid Nanoparticles with Improved RNA Delivery

• DOI: 10.1021/acs.nanolett.3c03345
• Publication Date: 2024-03-04T12:50:05Z
• Authors: Bram Bogaert; Aliona Debisschop; Thomas Ehouarne; Hannelore P. Van ...; Joyceline De Volder; An Jacobs; Eline Pottie; Riet De Rycke; Aurélie Crabbé; Pieter Mestdagh; Ine Lentacker; Guy G. Brusselle; Christophe Stove; Sandra Verstraelen; Tania Maes; Ken R. Bracke; Stefaan C. De Smedt; Koen Raemdonck
• Keywords: Mice; Cholesterol; lipid nanoparticles; siRNA; mRNA; cationic amphiphilic drugs; drug repurposing; combinationtherapy; inhalation therapy; nebulization; Liposomes; Medicine and Health Sciences; Animals; Humans; Nanoparticles; RNA, Small Interfering

The delivery of RNA across biological barriers can be achieved by encapsulation in lipid nanoparticles (LNPs). Cationic amphiphilic drugs (CADs) are pharmacologically diverse compounds with ionizable lipid-like features. In this work, we applied CADs as a fifth component state-of-the-art LNPs via microfluidic mixing. Improved cytosolic both siRNA and mRNA was partly replacing the cholesterol fraction CADs. could cross mucus layer mucus-producing air-liquid interface model human primary bronchial epithelial cells following nebulization. Moreover, CAD-LNPs demonstrated improved endothelial targeting intranasal administration mice, without marked pro-inflammatory signature. Importantly, quantification CAD-LNP molar composition, for nortriptyline, revealed gradual leakage CAD from formulation during LNP dialysis. Altogether, these data suggest that addition prior to rapid mixing process might have an impact on structure, performance LNPs.