NIR-Activated Spatiotemporally Controllable Nanoagent for Achieving Synergistic Gene-Chemo-Photothermal Therapy in Tumor Ablation

A rational combination of different therapeutic modalities within one single nanostructure is promising to enhance the therapeutic response, especially to achieve a synergistic therapeutic efficacy for tumor treatment. Herein, a near-infrared (NIR) photothermally activated nanoagent, which could achieve a spatially controllable codelivery of different curative molecules and a temporally controlled responsive release, was designed to perform effective gene-chemo-photothermal therapy of malignant tumors. The nanoagent consisted of a gold nanorod (AuNR) functionalized with mPEG, DNA, and small interfering RNA (siRNA). With the aid of aptamer AS1411-mediated recognition and endocytosis, the nanoagents were selectively delivered into cancer cells; subsequently, the photothermal conversion of AuNRs happened while under NIR irradiation, which successfully achieved an effective photothermal therapy, induced dehybridization of DNA duplexes, and simultaneously released doxorubicin (DOX) and siRNA. Then, the released siRNA silenced the expression of the multidrug resistance associated protein 1 (MRP1), the primary cause of the undesirable expelling of DOX in PC-3 cells, yielding a remarkable improvement in the efficiency of gene-chemo therapy. All of the results of in vitro and in vivo studies revealed that our prepared nanoagents exhibited an excellent performance in synergistic gene-chemo-photothermal therapy and successfully inhibited tumor growth. This work provides an interesting concept of a nanoscale therapeutic agent in achieving a dramatically enhanced therapeutic ability for tumor ablation, which benefits from the spatiotemporally controllable properties and the synergistic combination of chemotherapy, gene therapy, and photothermal therapy in one single nanoagent.