Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, 215123, China.
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China.
Adv Mater. 2021 Feb;33(7):e2007557. doi: 10.1002/adma.202007557. Epub 2021 Jan 14.
Despite the critical breakthrough achieved by immune checkpoint blockade (ICB), the clinical benefits are usually restricted by inefficient infiltration of immune cells and immune-associated adverse effects. Noninvasive aerosol inhalation, as a definitive procedure for treatment of respiratory diseases, for ICB immunotherapy against lung metastasis, has not been realized to the best knowledge. Herein, an inhaled immunotherapeutic chitosan (CS)-antibody complex is developed for immunotherapy against lung cancer. In this system, CS is used as a carrier to assemble with anti-programmed cell death protein ligand 1 (aPD-L1) to enable efficient transmucosal delivery. Moreover, CS exhibits adjuvant effects to drive potent immune responses via activating the cyclic-di-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Interestingly, repeated inhalation of CS/aPD-L1 complex can effectively activate the immune system by promoting the infiltration of different immune cells especially CD8 T cells around tumor lesions, and finally prolongs the survival of mice to 60 days. Thus, the work presents a unique aerosol inhalation delivery system for ICB antibody, which is promising for immunotherapy against lung metastasis without the concern of systemic toxicity.
尽管免疫检查点阻断（ICB）取得了重大突破，但临床获益通常受到免疫细胞浸润效率低下和免疫相关不良反应的限制。据目前所知，非侵入性气溶胶吸入作为治疗呼吸系统疾病的一种明确方法，尚未在针对肺癌转移的 ICB 免疫治疗中得到实现。本文开发了一种用于肺癌免疫治疗的吸入性免疫治疗壳聚糖（CS）-抗体复合物。在该系统中，CS 被用作载体与抗程序性细胞死亡蛋白配体 1（aPD-L1）组装，以实现高效的黏膜递药。此外，CS 通过激活环二鸟苷酸-腺苷酸合酶（cGAS）-干扰素基因刺激物（STING）途径发挥佐剂作用，从而驱动强烈的免疫反应。有趣的是，重复吸入 CS/aPD-L1 复合物可通过促进不同免疫细胞（特别是肿瘤病灶周围的 CD8 T 细胞）的浸润，有效激活免疫系统，最终将小鼠的存活期延长至 60 天。因此，该工作提出了一种用于 ICB 抗体的独特气溶胶吸入递药系统，有望在无需担心全身毒性的情况下用于免疫治疗肺癌转移。
