DNA Nanoassembly Modified Polydopamine@MnO₂ Nanoparticles: Enhancement of miRNA-21 Downregulation for Reversal of Breast Cancer Drug-Resistance

Downregulating oncogenic microRNAs (miRNAs) is an attractive strategy for reversing drug resistance in cancer therapy. Compared to antisense, DNAzyme (Dz) possesses advantages such as recyclability and stability. However, it still suffers from insufficient stability and inadequate endogenous cofactors. Herein, by using miRNA-21 (miR-21) as target, MCF-7/ADR as tumor model, a multi-modality, polyvalent, Spherical Nucleic Acids (SNAs)-type drug delivery system (DDS) was developed. A Y-DNA nanoassembly was synthesized, and directional immobilized on polydopamine@MnO₂ (PDM) nanoparticles. The Y-DNA contains two Dz sequences for cleaving miR-21, and a tumor-targeting aptamer. Doxorubicin was loaded at a loading rate of 23.33%. The DDS dramatically improved the Dz stability, self-supplied cofactors, efficiently targeted tumor tissues and cells. Additionally, it relieved hypoxia, depleted glutathione, generated reaction oxygen species, and transferred near-infrared light to heat. Consequently, highly responsive, and DNase resistant cleavage of miR-21 was realized. Intracellular miR-21 was efficiently downregulated. Doxorubicin was controllably and efficiently released. With the PDM@Y-DNA@D (Laser+) treatment, the cancer cell viability lowered to ≤3%, and tumor growth inhibition reached to 86%. Molecular mechanisms involved in the drug resistance reversal were investigated. The DDS provides a promisingly transformable therapeutic platform for drug resistant cancers, and for targeting other and multiple oncogenic miRNAs.