Gene-regulatory
biomolecules such as splice correcting oligonucleotides and anti-microRNA
oligonucleotides are important tools in the struggle to understand and treat
genetic disorders caused by defective gene expression or aberrant splicing. However,
oligonucleotides generally suffer from low bioavailability, hence requiring
efficient and non-toxic delivery vectors to reach their targets.
Cell-penetrating peptides constitute a promising category of carrier molecules
for intracellular delivery of bioactive cargo. In this study we present a novel
cell-penetrating peptide, PepFect15, comprising the previously reported
PepFect14 peptide modified with endosomolytic trifluoromethylquinoline moieties
to facilitate endosomal escape. Pepfect15 efficiently delivers both
splice-correcting oligonucleotides and anti-microRNA oligonucleotides into
cells through a non-covalent complexation strategy. The
peptide and its cargo form stable, negatively charged nanoparticles that are
taken up by cells largely through scavenger receptor type A mediated
endocytosis.