Y-Shaped Backbone-Rigidified DNA Tiles for the Construction of Supersized Nondeformable Tetrahedrons for Precise Cancer Therapies

Abstract

While engineered DNA nanoframeworks have been extensively exploited for delivery of diagnostic and therapeutic regents, DNA tiling-based DNA frameworks amenable to applications in living systems lag much behind. In this contribution, by developing a Y-shaped backbone-based DNA tiling technique, we assemble Y-shaped backbone-rigidified supersized DNA tetrahedrons (RDT) with 100% efficiency for precisely targeted tumor therapy. RDT displays unparalleled rigidness and unmatched resistance to nuclease degradation so that it almost does not deform under the force exerted by the atomic force microscopy tip, and the residual amount is not less than 90% upon incubating in biological media for 24 h, displaying at least 11.6 times enhanced degradation resistance. Without any targeting ligand, RDT enters the cancer cell in a targeted manner, and internalization specificity is up to 15.8. Moreover, 77% of RDT objects remain intact within living cells for 14 h. The drug loading content of RDT is improved by 4–8 times, and RDT almost 100% eliminates the unintended drug leakage in a stimulated physiological medium. Once systemically administrated into HeLa tumor-bearing mouse models, doxorubicin-loaded RDTs preferentially accumulate in tumor sites and efficiently suppress tumor growth without detectable off-target toxicity. The Y-DNA tiling technique offers invaluable insights into the development of structural DNA nanotechnology for precise medicine.

Superlarge, Rigidified DNA Tetrahedron with a Y-Shaped Backbone for Organizing Biomolecules Spatially and Maintaining Their Full Bioactivity

“…DNA tile assembly is often accomplished by a hierarchical method. In this approach, a small number of DNA oligonucleotides with a specially designed base sequence/length are assembled into sticky-end-contained DNA tiles and finally integrated into a user-defined nanoscale structure . The tile assembly strategy is simpler and more straightforward, but the assembly yield of most tile-assembly-based nano-objects is low, possibly due to the limited weak interaction between DNA components and direct exposure to attack from the surrounding environment .…”