Potentiating In Vivo Precision Cancer Therapy With Modularized Aptamer-Chemotherapeutics Conjugates Based on DNA Tiling-Mediated Structural Nanotechnology.

While DNA origami nanotubes have been often used in the biomedical field, the technical challenges in the assembly at large scale and the susceptibility to degradation limit their exploration for clinical application. In the current contribution, we propose a structural DNA nanotechnology (TMM) for the construction of a degradation-resistant DNA nanotube (DNT) via periodically tiling two structural modules (M) into a modularized (M) tubular DNA nano-architecture. The tube circumference is 118.6 nm, the tube length is 478 nm and the assembly efficiency is almost up to 90%. Upon installation of up-down tumor cell-binding aptamers onto each structural module in a highly precise manner, a protective outer layer was formed. Compared with Biotin-DNA nanowire, the relative nuclease degradation resistance of AS1411-DNT is improved by about 92-fold. Via using commercially synthesized 5-FU-embedded DNA components, we constructed a tumor cell-targeting therapeutic agent-loaded nanoconjugate, AS1411-DNT-5-FU, which exhibits significantly higher therapeutic outcomes than clinic free 5-FU in MCF-7 tumor-bearing mouse models without observable systemic toxicity. While DNA DNT holds great potential for precise drug delivery for cancer therapy, the modularization-based TMM structural DNA nanotechnology is expected to promote the development of next-generation multifunctional 3D-DNA nanostructures and clinical application in precision medicine.