尽管对肺癌的治疗取得了进展，但肺部粘膜屏障的存在仍然阻碍了治疗药物的渗透和扩散，极大限制了治疗效果。在本研究中，我们报告了一种新型可吸入的pH响应性四面体DNA纳米机，能够同时传递免疫调节性CpG寡核苷酸和PD-L1靶向拮抗DNA适配体（CP@TDN），以高效治疗肺转移癌。通过精确控制CpG和PD-L1适配体的比例，所得到的CP@TDN可在酸性肿瘤微环境下特异性释放PD-L1适配体，阻断PD-1/PD-L1免疫检查点轴，随后被抗原呈递细胞内吞，从而产生抗肿瘤免疫激活和抗肿瘤细胞因子的分泌。此外，通过吸入途径给予CP@TDN可使其在肺部高效沉积，显著增强肿瘤内积聚，这得益于DNA四面体介导的肺粘膜穿透作用。结果表明，CP@TDN可以通过诱导强大的抗肿瘤反应显著抑制转移性原位肺肿瘤的生长。因此，我们的研究提供了一种新颖的方法，利用生物相容性的DNA四面体作为吸入递送系统，以实现转移性肺癌的有效治疗。版权所有 © 2023 Elsevier Ltd. 保留所有权利。

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.Copyright © 2023 Elsevier Ltd. All rights reserved.