Endogenous Stimuli-Responsive Nucleus-Targeted Nanocarrier for Intracellular mRNA Imaging and Drug Delivery

Drug resistance arising from overexpressed efflux transporters increases the efflux of drugs and accordingly restricts the efficacy of chemotherapy. Advances in nanocarriers have provided potential strategies to cope with drug resistance. Herein, endogenous stimuli-responsive nucleus-targeted nanocarrier is developed for intracellular multidrug resistance protein 1 (MRP1) mRNA imaging and drug delivery. This nanocarrier (AuNP-mRS-DSs) is composed of three parts: (i) gold nanoparticle (AuNP), for loading DNA and quenching fluorescence; (ii) mRNA recognition sequence (mRS) modified on the surface of gold nanoparticle by gold-thiol bond, for the specific recognition of MRP1 mRNA; (iii) detachable subunit (DS), hybridized with Cy5-labeled DNA linker and nucleolin recognition motif and grafted onto mRS via the DNA linker for loading doxorubicin (Dox), binding to nucleolin, and reporting signal. First, nucleolin recognition motif of this nanocarrier targets nucleolin, which is overexpressed on cancer cells surface; subsequently, the whole nanocarrier enters the cell via nucleolin-mediated internalization. Subsequently, mRS will specifically recognize overexpressed MRP1 mRNA, leading to the release of trapped DS and followed by AuNP-quenched Cy5 fluorescence recovery. Finally, by translocation of nucleolin from cytoplasm to nucleus, the DS targets nucleus to delivery Dox. By intracellular fluorescence imaging, the differentiation of drug-resistant and nondrug-resistant cells could be achieved. Compared with free Dox (IC₅₀ > 8.00 μM), Dox-loaded AuNP-mRS-DSs (IC₅₀ = 2.20 μM) performed superior suppression efficacy toward drug-resistant cancer cells. Such a nanocarrier provides an effective strategy to synergistically sense and circumvent drug resistance, which may be exploited as a candidate for personalized medicine.