Nanoparticle‐Mediated Delivery of Inhaled Immunotherapeutics for Treating Lung Metastasis

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.