Nanoparticle based gene delivery systems holds great promise. Superparamagnetic iron oxide nanoparticles (SPIONs) are being heavily investigated due to good biocompatibility and added diagnostic potential, rendering such nanoparticles theranostic. Yet, commonly used cationic coatings for efficient delivery of such anionic cargos, results in significant toxicity limiting translation of the technology to the clinic. Here, we describe a highly biocompatible, small and non-cationic SPION-based theranostic nanoparticles as novel gene therapy agents. We propose for the first-time, the usage of the microRNA machinery RISC complex component Argonaute 2 (AGO2) protein as a microRNA stabilizing agent and a delivery vehicle. In this study, AGO2 protein-conjugated, anti-HER2 antibody-linked and fluorophore-tagged SPION nanoparticles were developed (SP-AH nanoparticles) and used as a carrier for an autophagy inhibitory microRNA, MIR376B. These functionalized nanoparticles selectively delivered an effective amount of the microRNA into HER2-positive breast cancer cell lines in vitro and in a xenograft nude mice model of breast cancer in vivo, and successfully blocked autophagy. Furthermore, combination of the chemotherapy agent cisplatin with MIR376B-loaded SP-AH nanoparticles increased the efficacy of the anti-cancer treatment both in vitro in cells and in vivo in the nude mice. Therefore, we propose that AGO2 protein conjugated SPIONs are a new class of theranostic nanoparticles and can be efficiently used as innovative, non-cationic, non-toxic gene therapy tools for targeted therapy of cancer.

中文翻译：

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用由AGO2偶联的纳米颗粒携带的自噬抑制性microRNA治疗乳腺癌。

基于纳米粒子的基因传递系统具有广阔的前景。由于良好的生物相容性和增加的诊断潜力，正对超顺磁性氧化铁纳米颗粒（SPIONs）进行大量研究，从而使这种纳米颗粒成为治疗性的。然而，用于有效递送此类阴离子货物的常用阳离子涂料导致明显的毒性，限制了该技术向临床的转化。在这里，我们描述了一种高度生物相容性的，基于小和非阳离子的SPION的治疗纳米颗粒，作为新型基因治疗剂。我们首次建议使用microRNA机械RISC复杂成分Argonaute 2（AGO2）蛋白作为microRNA稳定剂和传递载体。在这项研究中，AGO2蛋白缀合，开发了抗HER2抗体连接和荧光团标记的SPION纳米颗粒（SP-AH纳米颗粒），并用作自噬抑制性microRNA MIR376B的载体。这些功能化的纳米粒子在体外和在乳腺癌的异种移植裸鼠模型中选择性地将有效量的microRNA递送到HER2阳性乳腺癌细胞系中，并成功地阻止了自噬。此外，化学疗法顺铂与MIR376B负载的SP-AH纳米颗粒的组合提高了细胞体外和裸鼠体内抗癌治疗的功效。因此，我们提出，缀合了AGO2蛋白的SPIONs是一类新型的治疗性纳米颗粒，可以有效地用作针对癌症的靶向治疗的创新，非阳离子，无毒的基因治疗工具。