Multifunctional Molecular Beacon Micelles for Intracellular mRNA Imaging and Synergistic Therapy in Multidrug‐Resistant Cancer Cells

Multidrug resistance (MDR) resulting from overexpression of P‐glycoprotein (Pgp) transporters increases the drug efflux and thereby limits the chemotherapeutic efficacy. It is desirable to administer both an MDR1 gene silencer and a chemotherapeutic agent in a sequential way to generate a synergistic therapeutic effect in multidrug‐resistant cancer cells. Herein, an anti‐MDR1 molecular beacon (MB)‐based micelle (a‐MBM) nanosystem is rationally designed. It is composed of a diacyllipid core densely packed with an MB corona. One of Pgp‐transportable agents, doxorubicin (DOX), is encapsulated in the hydrophobic core of the micelle and in the stem sequence of MB. The a‐MBM‐DOX nanosystem shows an efficient self‐delivery, enhanced enzymatic stability, excellent target selectivity, and high drug‐loading capacity. With its relatively high enzymatic stability, a‐MBM‐DOX initially facilitates intracellular MDR1 mRNA imaging to distinguish multidrug‐resistant and non‐multidrug‐resistant cells and subsequently downregulates the MDR1 gene expression owing to an antisense effect. After that, the MB corona is degraded, destroying the micellar nanostructure and releasing DOX, which result in a high accumulation of DOX in OVCAR8/ADR cells and a high chemotherapeutic efficacy because of successful restoration of drug sensitivity. This micelle approach has the potential for both visualizing MDR1 mRNA and overcoming MDR in a sequential and synergistic way.