肺癌是发病率与死亡率最高的恶性肿瘤，EGFR-TKI已成为目前肺癌治疗中的重要手段，但患者对三代EGFR-TKI产生耐药后，往往病情进展迅速；其中EGFR-C797S突变是三代EGFR-TKI重要的耐药机制，目前尚无有效治疗方案。本课题组前期研究发现，通过设计合成特异性的miRNA可有效降低EGFR-C797S突变型肺癌细胞株中的EGFR表达水平及磷酸化水平，从而抑制肿瘤细胞增殖。结合近年来具有广阔医学应用前景的自组装DNA纳米材料，我们提出一种新型的DNA 纳米材料组装策略，其特点包括铁离子（Fe2+）介导组装、可携带特异性的miRNA、良好的生物兼容性等。其可通过Fe2+诱导肺癌细胞铁死亡，所携带特异性miRNA靶向EGFR-C797S位点，协同杀伤该突变型肺癌细胞；通过体内与体外实验系统地研究该纳米材料治疗效果及其协同作用机制，为三代EGFR-TKI耐药型肺癌治疗提供新的思路与策略。

Lung cancer is a malignant tumor with the highest morbidity and mortality worldwide. At present, EGFR-TKIs have become an important means of lung cancer treatment. However, when the patients develop resistance to third generation EGFR-TKIs, their conditions usually deteriorate rapidly. EGFR Cys797Ser (C797S) mutation, located within the tyrosine kinase domain, was reported to be a mainly mechanism of resistance to third generation EGFR-TKIs, and there is no effective treatment for this mutation at present. Our previous study found that the designed specific miRNA can effectively reduce the expression level and phosphorylation level of EGFR in lung cancer cell lines with EGFR-C797S mutant, thus inhibiting the proliferation of these cells. In consideration of self-assembled DNA nanomaterials have been proved with broad prospects of medical application in recent years, we propose a new strategy of self-assembly DNA nanomaterials. The characteristics of that include iron ion (Fe2+) mediated assembly, carrying specific miRNA, great biological compatibility, etc. It can induce ferroptosis of lung cancer cells through Fe2+, and the specific miRNA carried can target the EGFR-C797S mutant site and silence the expression of EGFR gene with C797S mutant, synergistically kill EGFR-C797S mutant lung cancer cells. The therapeutic effect and synergistic mechanism of the nanomaterial were systematically studied through in vivo and in vitro experiments. The aim of this project is to provide new ideas and strategies for the treatment of third-generation EGFR-TKIs drug-resistant lung cancer.