Inhibiting DNA Sensing Pathway using Chitosan Nanoparticle to Control Lung Inflammation during Steroid Resistant Asthma

Cyclic GMP-AMP synthases (cGAS) and Stimulator of interferon genes (STING) pathway has recently emerged as an interesting and effective target to control chronic inflammation. This pathway is mostly triggered by DNA damage, the level of which is upregulated in chronically inflamed tissue, including lung tissue during asthma. Activation of this pathway induces the production of pro-inflammatory mediators, mostly type I interferons (IFNs). The central role of STING in the immunoinflammatory process has initiated an intense research for the identification and development of STING inhibitors. H-151 is a recently discovered potent, irreversible, and selective inhibitor of STING (Haag et al., 2018). H-151 was successfully used to control inflammation in an autoimmune murine model. However, the systemic administration of H-151 could result in non-specific side effects which can be prevented by the targeted delivery of H-151 using a nanoparticle approach.

In this proposal, we aim to control lung inflammation in an asthma mouse model by blocking the STING pathway using a NP loaded with H-151 and targeted to lung tissue.