Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
Department of Medicine, Division of Engineering in Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Nat Nanotechnol. 2023 Nov;18(11):1351-1363. doi: 10.1038/s41565-023-01447-7. Epub 2023 Jul 13.
Intravenously administered cyclic dinucleotides and other STING agonists are hampered by low cellular uptake and poor circulatory half-life. Here we report the covalent conjugation of cyclic dinucleotides to poly(β-amino ester) nanoparticles through a cathepsin-sensitive linker. This is shown to increase stability and loading, thereby expanding the therapeutic window in multiple syngeneic tumour models, enabling the study of how the long-term fate of the nanoparticles affects the immune response. In a melanoma mouse model, primary tumour clearance depends on the STING signalling by host cells-rather than cancer cells-and immune memory depends on the spleen. The cancer cells act as a depot for the nanoparticles, releasing them over time to activate nearby immune cells to control tumour growth. Collectively, this work highlights the importance of nanoparticle structure and nano-biointeractions in controlling immunotherapy efficacy.
静脉注射的环状二核苷酸和其他 STING 激动剂由于细胞摄取率低和循环半衰期短而受到阻碍。在这里，我们报告了通过组织蛋白酶敏感的连接物将环状二核苷酸共价连接到聚（β-氨基酯）纳米颗粒上。这被证明可以提高稳定性和载药量，从而在多种同基因肿瘤模型中扩大治疗窗口，使研究纳米颗粒的长期命运如何影响免疫反应成为可能。在黑色素瘤小鼠模型中，原发性肿瘤的清除取决于宿主细胞而非癌细胞中的 STING 信号，而免疫记忆取决于脾脏。癌细胞充当纳米颗粒的储存库，随着时间的推移释放它们，以激活附近的免疫细胞来控制肿瘤生长。总的来说，这项工作强调了纳米颗粒结构和纳米生物相互作用在控制免疫治疗效果方面的重要性。
