DNA Origami as a Carrier for Circumvention of Drug Resistance

TLDR

Effective delivery of anti‑cancer drugs remains a challenge; nanoparticles offer high delivery efficiency but lack biocompatibility and spatially addressable surfaces, limiting their use. The study introduces a DNA origami nanostructure drug carrier to overcome these nanoparticle limitations. The carrier is formed by self‑assembled DNA origami onto which doxorubicin is intercalated, and the complex is thought to inhibit lysosomal acidification, redistributing the drug to action sites. The DNA origami–doxorubicin complex achieved high loading efficiency, enhanced cellular uptake, and markedly increased cytotoxicity against both regular and doxorubicin‑resistant MCF7 cells, reversing resistance and demonstrating strong therapeutic potential.

Abstract

Although a multitude of promising anti-cancer drugs have been developed over the past 50 years, effective delivery of the drugs to diseased cells remains a challenge. Recently, nanoparticles have been used as drug delivery vehicles due to their high delivery efficiencies and the possibility to circumvent cellular drug resistance. However, the lack of biocompatibility and inability to engineer spatially addressable surfaces for multi-functional activity remains an obstacle to their widespread use. Here we present a novel drug carrier system based on self-assembled, spatially addressable DNA origami nanostructures that confronts these limitations. Doxorubicin, a well-known anti-cancer drug, was non-covalently attached to DNA origami nanostructures through intercalation. A high level of drug loading efficiency was achieved, and the complex exhibited prominent cytotoxicity not only to regular human breast adenocarcinoma cancer cells (MCF 7), but more importantly to doxorubicin-resistant cancer cells, inducing a remarkable reversal of phenotype resistance. With the DNA origami drug delivery vehicles, the cellular internalization of doxorubicin was increased, which contributed to the significant enhancement of cell-killing activity to doxorubicin-resistant MCF 7 cells. Presumably, the activity of doxorubicin-loaded DNA origami inhibits lysosomal acidification, resulting in cellular redistribution of the drug to action sites. Our results suggest that DNA origami has immense potential as an efficient, biocompatible drug carrier and delivery vehicle in the treatment of cancer.