3 research outputs found
Selective Replacement of Cholesterol with Cationic Amphiphilic Drugs Enables the Design of Lipid Nanoparticles with Improved RNA Delivery
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
of state-of-the-art LNPs via microfluidic mixing. Improved cytosolic
delivery of both siRNA and mRNA was achieved by partly replacing the
cholesterol fraction of LNPs with CADs. The LNPs could cross the mucus
layer in a mucus-producing air–liquid interface model of human
primary bronchial epithelial cells following nebulization. Moreover,
CAD-LNPs demonstrated improved epithelial and endothelial targeting
following intranasal administration in mice, without a marked pro-inflammatory
signature. Importantly, quantification of the CAD-LNP molar composition,
as demonstrated for nortriptyline, revealed a gradual leakage of the
CAD from the formulation during LNP dialysis. Altogether, these data
suggest that the addition of a CAD prior to the rapid mixing process
might have an impact on the composition, structure, and performance
of LNPs