A DNA tetrahedron is employed for efficient delivery of doxorubicin into drug-resistant breast cancer cells. The drug delivered with the DNA nanoconstruct is considerably cytotoxic, whereas free doxorubicin is virtually non-cytotoxic for the drug-resistant cells. Thus, the DNA tetrahedron, made of the inherently natural and biocompatible material, can be a good candidate for the drug carrier to overcome MDR in cancer cells.

Cell penetrating peptides (CPPs) are peptides that can be translocated into cells and used as a carrier platform for the intracellular uptake of cargo molecules. Subject to the source of CPP sequences and their positively charged nature, the cytotoxicity and immunogenicity of conventional CPPs needs to be optimized to expand their utility for biomedical applications. In addition to these safety issues, the stability of CPPs needs to be addressed since their positively charged residues are prone to interact with the biological milieu. As an effort to overcome these limitations of the current CPP technology, we isolated CPP candidate sequences and synthesized peptides from twelve isoforms of annexin, a family of membrane-interacting human proteins. The candidate screen returned a CPP rich in hydrophobic residues that showed more efficient cellular uptake than TAT-CPP. We then investigated the uptake mechanism, subcellular localization and biophysical properties of the newly found CPP, verifying low cytotoxicity, long-term serum stability and non-immunogenicity. Finally, model proteins conjugated to this peptide were successfully delivered into mammalian cells both in vitro and in vivo, indicating a potential use of the peptide as a carrier for the delivery of macromolecular cargos.

DNA nanoconstructs are a potential drug carrier with high biocompatibility. They are promising particularly when therapeutic nucleic acids are the cargos to be delivered, since both the carrier and the cargo are nucleic acids which can be designed, synthesized and assembled in a seamless feature without using post-synthetic conjugation chemistry. However, the unwanted base-paring events between the cargo and the carrier may potentially disturb the desired structure of the cargo-loaded carrier. To address this concern, we propose a DNA nanocarrier composed of L-DNA strands having a bioorthogonal base-paring system. The study presented here provides useful properties of L-DNA as a backbone for the DNA nanocarrier and demonstrates superiority of L-DNA over the natural D-DNA backbone in the delivery of an anti-proliferative aptamer as well as in the construction of the cargo-carrier assembly.