Intracellular Delivery of Oligonucleotide Conjugates and Dendrimer Complexes

: Enhancing the delivery of antisense and siRNA molecules to cells and tissues is a key issue for oligonucleotide therapeutics. Cell‐penetrating peptides (CPPs) have the ability to convey linked “cargo” molecules into the cytosol; thus we have explored the use of CPPs as delivery agents for oligonucleotides. We have extensively evaluated CPP–oligonucleotide conjugates, and have recently begun to explore the use of CPP–dendrimer–oligonucleotide complexes. We have found that CPP‐antisense oligonucleotide conjugates can be taken up by cells and can effectively modify gene expression in cell culture and in tissues. Although not as potent in cell culture as cationic lipid delivery agents, CPP–oligonucleotide conjugates offer the advantage of being molecules rather than particles, and may have substantial advantages over particle‐based delivery in the in vivo setting.