Gene therapy based on transfection of RNAs/DNAs offers tremendous promise for
tumor treatment. However, the relatively weak therapeutic efficiency of current genetic nanohybrids in vivo has limited the application of this strategy. Herein, we fabricated multifunctional core-shell-corona nanohybrids by combining cascaded
theranostics for enhanced gene therapy. The nanohybrids consist of
polydopamine-modified Fe3O4 nanoparticles as core, anti-miRNA-21
oligonucleotides (anti-
miRNA) strands as shell, and
doxorubicin (DOX)-conjugated DNA-8pb (DOX-DNA-8bp) as corona. The
polydopamine/Fe3O4 core not only serves as an active agent for local
photothermal therapy under NIR irradiation, but it also provides magnetic targeting to
tumor tissue for accurate treatment, which could enhance the
therapeutic effect and reduce the undesired side effects to healthy tissues. The DOX-DNA-8bp corona was grafted on the anti-
miRNA shell through base pairing, which could be replaced by overexpressed miRNA-21 in
tumor cells due to the strong interaction between miRNA-21 and anti-
miRNA, resulting in
tumor-specific gene therapy through tumorigenic miRNA-21 consumption and
tumor selective
chemotherapy through miRNA-21-triggered DOX-DNA-8bp release in
tumor cells. Moreover, the intelligent controlled release system can gradually stop the release of DOX to prevent side effects caused by
drug overdose, once sufficient damage of
tumor cells has occurred, due to the downregulation of miRNA-21. The results of both in vitro and in vivo analyses showed that the nanohybrids combining cascaded chemo-photo-gene therapy could effectively inhibit
tumor growth, promote the survival of
tumor-bearing mice, and show no visible adverse effects on these mice, resulting in a promising nanoplatform for
tumor treatment. STATEMENT OF SIGNIFICANCE: Gene therapy based on transfection of RNAs/DNAs offers tremendous promise for
cancer treatment. However, the relatively weak therapeutic efficiency of current genetic nanovectors in vivo that results in insufficient
tumor targeting and easy decomposition/elimination of RNAs/DNAs during
therapy has limited its application. Although some approaches have combined photothermal agents or
antitumor drugs with
RNA/
DNA nanocarriers to achieve better treatment, the spatiotemporal differences in
photothermal therapy,
chemotherapy, and gene therapy using current nanohybrids may hinder their synergistic effect. In the present study, we fabricated multifunctional core-shell-corona nanohybrids (Fe3O4@PDA@anti-
miRNA/
DNA) to simultaneously perform on-demand
photothermal therapy, miR-21-triggered
chemotherapy, and miR-21-dependent gene therapy at the same location, which can achieve an efficient synergistic effect for precise and effective
tumor treatment.