Fan Qin, Li Zhihao, Yin Jue, Xie Mo, Cui Meirong, Fan Chunhai, Wang Lianhui, Chao Jie
State Key Laboratory for Organic Electronics & Information Displays (KLOEID), Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials (IAM) and School of Materials Science and Engineering, Nanjing University of Posts & Telecommunications, Nanjing 210000, China.
School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules and National Center for Translational Medicine, Shanghai Jiao Tong University, Shanghai 200240, China.
Biomaterials. 2023 Oct;301:122283. doi: 10.1016/j.biomaterials.2023.122283. Epub 2023 Aug 24.
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.
尽管肺癌治疗取得了进展，但肺部黏膜屏障的存在仍阻碍了治疗药物的渗透和扩散，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响应性四面体DNA纳米机器，其同时递送免疫调节性CpG寡核苷酸和靶向PD-L1的拮抗DNA适配体（CP@TDN），用于高效治疗肺转移性癌症。通过精确控制CpG和PD-L1适配体的比例，所获得的CP@TDN能够在酸性肿瘤微环境中特异性释放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，以产生抗肿瘤免疫激活并分泌抗肿瘤细胞因子。此外，CP@TDN的吸入给药显示出高效的肺部沉积，肿瘤内蓄积显著增强，这归因于DNA四面体介导的肺黏膜穿透。结果，CP@TDN可通过诱导强烈的抗肿瘤反应，显著抑制转移性原位肺肿瘤的生长。因此，我们的工作提出了一种有吸引力的方法，即借助生物相容性DNA四面体作为吸入给药系统，有效治疗转移性肺癌。
