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Dual MicroRNA-Triggered Drug Release System for Combined Chemo- and Gene Therapy with Logic Operation.

Combination therapy via stimuli-responsive drug release is known to improve treatment efficacy and minimize side effect. However, the use of low-abundant cancer biomarkers as molecular triggers to induce efficient drug release for combination therapy still remains a challenge. Herein, we developed a dual microRNA-responsive drug nanocarrier for catalytic release of doxorubicin (Dox) and small interfering RNA (siRNA) in cancerous cells for combined chemo- and gene therapy with logic operation. The nanocarrier is constructed by assembling two duplex of DNA/RNA and Dox molecules onto DNA-functionalized gold nanoparticles (GNP). Two microRNA molecules (miRNA-21 and miRNA-10b overexpressed in MDA-MB-231) could alternatively catalyze the disassembly of the nanocarrier through thermodynamically driven entropy gain process, during which Dox molecules are released and the two pairs of released DNA/RNA duplex hybridize to generate siRNA (siBcl-2) in situ by strand displacement reactions (SDR). Quantum dots (QDs) are used to track the process in living cells. The AND logic gate-based drug release system allows effective treatment of specific cancer cell types according to miRNAs expression pattern. This strategy represents an effective means to overcome multi-drug resistance (MDR) and improve therapeutic effects.