Abstract：
Despite advancements in the treatment of pulmonary cancer, the existence of mucosal barriers in lung still hampered the penetration and diffusion of therapeutic agents and greatly limited the therapeutic benefits. In this work, we reported a novel inhalable pH-responsive tetrahedral DNA nanomachines with simultaneous delivery of immunomodulatory CpG oligonucleotide and PD-L1-targeting antagonistic DNA aptamer (CP@TDN) for efficient treatment of pulmonary metastatic cancer. By precisely controlling the ratios of CpG and PD-L1 aptamer, the obtained CP@TDN could specifically release PD-L1 aptamer to block PD-1/PD-L1 immune checkpoint axis in acidic tumor microenvironment, followed by endocytosis by antigen-presenting cells to generate anti-tumor immune activation and secretion of anti-tumor cytokines. Moreover, inhalation delivery of CP@TDN showed highly-efficient lung deposition with greatly enhanced intratumoral accumulation, ascribing to the DNA tetrahedron-mediated penetration of pulmonary mucosa. Resultantly, CP@TDN could significantly inhibit the growth of metastatic orthotopic lung tumors via the induction of robust antitumor responses. Therefore, our work presents an attractive approach by virtue of biocompatible DNA tetrahedron as the inhalation delivery system for effective treatment of metastatic lung cancer.
摘要：
尽管肺癌的治疗取得了进展，肺粘膜屏障的存在仍然阻碍了治疗剂的渗透和扩散，并极大地限制了治疗效果。在这项工作中,我们报道了一种新型的可吸入pH响应四面体DNA纳米机器,同时递送免疫调节CpG寡核苷酸和PD-L1靶向拮抗DNA适体(CP@TDN),可有效治疗肺转移癌.通过精确控制CpG和PD-L1适体的比例，获得的CP@TDN可以特异性释放PD-L1适体，阻断酸性肿瘤微环境中的PD-1/PD-L1免疫检查点轴，然后通过抗原呈递细胞内吞产生抗肿瘤免疫激活和分泌抗肿瘤细胞因子。此外，吸入递送CP@TDN显示高效的肺沉积与极大增强的肿瘤内积累,归因于DNA四面体介导的肺粘膜渗透。结果，CP@TDN可以通过诱导强烈的抗肿瘤反应显着抑制转移性原位肺癌的生长。因此,我们的工作通过生物相容性DNA四面体作为有效治疗转移性肺癌的吸入给药系统，提出了一种有吸引力的方法。
