DNA Nanoclew-Mediated Drug Deliver

The characteristic microenvironments of diseased areas, such as acidity and overexpressed enzymes, constitute both challenges and opportunities for targeted delivery of therapeutics. Advances in material chemistry have expanded the tool box available to design physiological signal-responsive drug delivery systems through customizing the size, shape, charge, and surface ligands of drug delivery carriers. DNA is a natural carrier to store and transmit genetic information. However, the polymeric nature of DNA also makes it a versatile material that could be programmed to load a large variety of therapeutic molecules through interactions like intercalation, conjugation, hybridization or adsorption. The degradability of DNA in vivo also makes it a promisiing material that could be readily cleared from the biological system.;Here, we have adopted a facile DNA synthesis technique termed rolling-circle amplification to prepare programmable single stranded DNA that could self-assemble into compact nanoparticles termed DNA nanoclew (NC). We explored the DNA NC as a platform nanocarrier for the delivery of various types of therapeutics, including an anticancer chemotherapeutic drug, cancer cell apoptosis inducing cytokine and genome editing ribonucleoprotein. To deliver the chemotherapeutic doxorubicin, the drug was intercalated into the DNA NC. DNase that could cleave the DNA NC for drug release was encapsulated in a cationic and acid degradable nanocapsule, which was assembled onto the DNA NC through electrostatic interaction. The nanoassembly could efficiently release the loaded drug in response to tumor associated acidity. To deliver the genome editing tool CRISPR-Cas9 into the nuclei of targeted cells, the DNA NC was programmed to be complementary to the guiding RNA of the ribonucleoprotein and a cationic polymer shell was coated for facilitated endosome escape. Balancing the interaction between DNA NC and the ribonucleoprotein dramatically boosted the genome editing efficacy. To deliver the cytokine tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) to the plasma membrane of cancer cells. The TRAIL was loaded into two complementary DNA NC and the contact of the two DNA NC was controlled through a liposome shell that could be degraded by the tumor associated PLA2. Release of the TRAIL loaded DNA NCs from the liposomes led to the shape transformation of the carrier from nanoparticle to microfibers, inhibiting cellular uptake of TRAIL and enhancing its apoptosis signaling on plasma membrane.