Three-in-one DNA nanowheels for simultaneous tumor regression and drug resistance prevention in breast cancer model

Herein, we proposed novel three-in-one DNA nanowheels with simultaneous chemo and gene therapy to treat tumor, especially to prevent simultaneous drug resistance, which could be disassembled via a cascaded hybridization reactions triggered by the highly expressed microRNA in cancer cells for smart and efficient cancer therapy. Typically, with breast cancer as a model, microRNA 21 could trigger the self-disassembly of DNA nanowheel 1 via hybridization with a specially designed oligonucleotide (anti-microRNA 21) in DNA nanowheel 1, releasing another special oligonucleotide (Contact sequence) to trigger the self-disassembly of DNA nanowheel 2 with releasing of a special oligonucleotide (anti-Contact sequence) to trigger the self-disassembly of DNA nanowheel 1 cyclically, and thus the cascaded hybridization reactions with three-in-one anti-cancer functions could be generated based on three main therapeutic effects via releasing doxorubicin to inhibit macromolecular biosynthesis, antisense oligonucleotide of microRNA 21 to activate the apoptotic cell pathway and antisense oligonucleotide of MDR1 to prevent the drug resistance respectively. As expected, the proposed method showed improved therapeutic efficacy on the cancer cells with about 80% apoptosis ratio, especially on the drug resistant cancer cells with about 75% apoptosis ratio, compared with that in the conventional anti-cancer systems of about 70% on cancer cells and below 40% on drug resistant cancer cells, respectively. Most importantly, this strategy opened the door for generation of complex functional DNA-based structures for target triggering drugs releasing system combining with chemo- and gene-therapy to generate tumor regression and prevent drug resistance with an optimized therapeutic efficacy, providing a new avenue for efficient cancer treatment, especially drug resistant cancers.