Beyond chloroquine: Cationic amphiphilic drugs as endosomal escape enhancers for nucleic acid therapeutics

Nucleic acid (NA) therapeutics have the potential to treat or prevent a myriad of diseases but generally require cytosolic delivery to be functional. NA drugs are therefore often encapsulated into delivery systems that mediate effective endocytic uptake by target cells, but unfortunately often display limited endosomal escape efficiency. This review will focus on the potential of repurposing cationic amphiphilic drugs (CADs) to enhance endosomal escape. In general terms, CADs are small molecules with one or more hydrophobic groups and a polar domain containing a basic amine. CADs have been reported to accumulate in acidified intracellular compartments (e.g., endosomes and lysosomes), integrate in cellular membranes and alter endosomal trafficking pathways, ultimately resulting in improved cytosolic release of the endocytosed cargo. As many CADs are widely used drugs, their repurposing offers opportunities for combination therapies with NAs.