用于肿瘤血管栓塞治疗的智能型DNA纳米机器人

Malignant cancer is one of the major threats for human health. In the clinical practice, surgery, radiotherapy and chemotherapy are the major approaches for cancer treatment. However, once diagnosed, most patients are already in advanced stage with less possibility of surgery. Besides, radiotherapy and chemotherapy usually bring patients with severe systemic side effects, especially myelosuppression. Therefore, new strategies with high efficiency and low side effects are urgently needed to be explored. Rapid tumor growth is highly dependent on the angiogenesis and blood supply, blocking tumor blood vessels to starve tumor cells to death is therefore an effective tumor therapeutic strategy. From 1978, Prof. Yamada suggested the usage of transcatheter arterial chemoembolization (TACE) for the treatment of unresectable hepatocellular carcinoma, various truncated tissue factor based tumor embolization therapeutics were developed and realized highly effective anti-tumor activity, such as pHLIP-Ttf, CREKA-Ttf, chTNT-3-tTF, chTV-1-tTF and RGD-tTF. The coagulation protease thrombin is able to efficiently induce the formation of thrombus through inducing platelet activation and converting fibrinogen to fibrin network. However, the short half-life and nonspecific thrombus induction in the circulation limit thrombin application for tumor embolization therapy. Therefore, developing new techniques for tumor-specially delivering thrombin to tumor vessels are urgently needed to introduce it into tumor therapy. The rapid development of DNA origami technology, with highly controlled synthesis and functionalization, offers a great possibility to achieve this purpose. In previous works, several intelligent DNA nanostructures were used to load chemotherapeutics or functional proteins and achieved controlled drug release. However, none of them was successfully applied for in vivo treatment of mammal diseases. In current work, we developed an intelligent tumor-targeting nanorobot which carried thrombin molecules inside and recognized tumor endothelium specific marker nucleolin to unfold thrombin. When intravenously injected into tumor-bearing mice, the DNA nanorobot was able to efficiently target to tumor tissue and induce local thrombus formation. Subsequently, this nanorobot lead to tumor necrosis in a large scale and significantly inhibited tumor growth in B16 melanoma, MDA-MB-231 breast cancer, SK-OV3 ovarian cancer and Kras mutation lung cancer models. Safety evaluation in mice and bama miniature pigs indicated the nanorobot has a good in vivo tolerance. This kind of DNA nanorobotic systems with targeting and triggered release properties inspires the design of novel cancer therapeutics and may benefit the precision medicine in the future research. Based on our work, we herein summarized recent progress of this field at home and abroad and particularly made a brief perspective about the development of DNA nanorobots. We hope this progress report can provide a reference for the future design of DNA nanorobots in the field of tumor embolism therapy.