Site-specific inhibition of neutrophilic inflammation by low-dose nanotherapy for immunoregulatory treatment of asthma

Abstract

Asthma, one of the most common lung diseases, remains a serious global health problem. Currently there is still an urgent need for effective and safe therapies against severe asthma. Neutrophil extracellular traps (NETs) have emerged as a new therapeutic target for asthma, while precision regulation of NETs is highly challenging. Here, we report site-specific attenuation of neutrophilic inflammation in the lungs via a cyclic oligosaccharide-derived nanotherapy (termed TPCN) for targeted treatment of asthma. Either intravenous or inhaled TPCN can distribute in lung neutrophils of asthmatic mice, thereby significantly mitigating oxidative stress, suppressing inflammatory responses, reversing airway remodelling, and improving pulmonary function in mice with allergic/neutrophilic asthma. Notably, TPCN is effective even at an actual inhalation dose of 0.06–0.07 mg/kg. Mechanistically, TPCN alleviates eosinophilic asthma by directly attenuating neutrophil-mediated T helper 2 (Th2) cell responses. For neutrophilic asthma, a typical phenotype of severe asthma, efficacies of TPCN are achieved by inhibiting the reactive oxygen species (ROS)-induced formation of NETs, which further promotes immune homeostasis via regulating the balance of regulatory T (Treg) and T helper 17 (Th17) cells. Thus, TPCN holds great promise for precision therapy of eosinophilic and neutrophilic asthma, while the ROS-NETs-Treg/Th17 pathway can function as intriguing therapeutic targets for the treatment of severe asthma and other neutrophil-mediated inflammatory diseases.