School of Chemical Engineering and Technology, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, Shenzhen Research Institute, Xi'an Jiao Tong University, Xi'an, 714049, China; Xi'an Jiao Tong University Shenzhen Research School, High-Tech Zone, Shenzhen, 518057, China.
Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology & Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health & NMPA Key Laboratory for Dental Materials, China.
Acta Biomater. 2021 Jul 1;128:408-419. doi: 10.1016/j.actbio.2021.04.019. Epub 2021 Apr 18.
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 FeO 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/FeO 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 (FeO@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.
基于 RNA/DNA 转染的基因治疗为肿瘤治疗带来了巨大的希望。然而，目前遗传纳米载体在体内的治疗效率相对较低，导致肿瘤靶向性不足，以及在治疗过程中 RNA/DNA 容易分解/消除，限制了其应用。尽管一些方法已经将光热剂或抗肿瘤药物与 RNA/DNA 纳米载体结合，以实现更好的治疗效果，但目前纳米杂化物中光热治疗、化学治疗和基因治疗的时空差异可能会阻碍它们的协同作用。在本研究中，我们构建了多功能核壳冠状纳米杂化物（FeO@PDA@anti-miRNA/DNA），可在同一部位按需进行光热治疗、miR-21 触发的化学治疗和 miR-21 依赖性基因治疗，从而实现精确有效的肿瘤治疗的高效协同效应。
