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

Combination therapy via stimulus-responsive drug release is known to improve treatment efficacy and minimize side effects. However, the use of low-abundance 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 chemotherapy and gene therapy with logic operation. The nanocarrier is constructed by assembling two duplexes of DNA/RNA and Dox molecules onto DNA-functionalized gold nanoparticles. Two microRNA molecules (miRNA-21 and miRNA-10b overexpressed in MDA-MB-231) could alternatively catalyze the disassembly of the nanocarrier through a 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. Quantum dots 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 miRNA expression patterns. This strategy represents an effective means to overcome multidrug resistance and improve therapeutic effects.