Development of airway epithelial targeted nanoparticles loaded with TLR7 agonist for asthma therapy

Acute asthma flares represent the major cause of healthcare resource consumption and prevention of acute asthma exacerbation remains a major currently unmet therapeutic need in asthma control. Respiratory viruses, most often rhinoviruses (RVs), are the most frequent trigger of acute asthma exacerbations. Airway epithelial cells (AECs) are the site RV infection and initiate the host response to infection which is a key determinant of disease outcome. Endosomal toll like receptor 7 (TLR7) is a potential therapeutic target for asthma exacerbations as stimulation of TLR7 improves antiviral response via induction of type I/ type III interferons (IFNs) and interferon-stimulated genes (ISGs). The challenge is to achieve efficient delivery of TLR7 agonists to activate antiviral immunity in infected AECs. Targeted TLR7 activation in AECs is critical as stimulation of TLR7 in resident immune cells may lead to unwanted induction of pro-inflammatory response. We hypothesized that AEC-targeting nanoparticles (AEC-NPs) offer a solution to this challenge by enabling AEC-targeted delivery of TLR7 agonists to boost antiviral immunity and subsequently inhibit viral replication. In this thesis, we developed and optimised the AEC-NP delivery system and confirmed its targeting specificity in human bronchial epithelial cells. The optimised AEC-NPs were able to efficiently deliver TLR7 agonist CL264 and boost antiviral immune response in both submerged monolayer culture and primary bronchial epithelial cells (from heathy donors and patients with asthma) grown in air-liquid interface (ALI) culture. Finally, the pharmacological response and inflammatory profile of CL264-loaded AEC-NPs were evaluated in vivo.