Regulation of cGAS-STING pathway with inhalable nanozyme in acute lung injury

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions marked by severe inflammation, oxidative stress, and disruption of the alveolar-capillary barrier. The limited efficacy of current therapies highlights the urgent need for novel approaches targeting key pathological mechanisms. Excessive generation of reactive oxygen species (ROS) and resulting cascade of amplified inflammatory responses is a key factor in the progression of ALI/ARDS. Herein, we successfully regulated the immune homeostasis-mediated inflammatory response to alleviate ALI based on the inhalable CoAl-LDH (CAL) nanosheets with good biocompatibility and exciting ROS scavenging capabilities. Transcriptomic analysis combined with single-cell sequencing reanalysis revealed, for the first time, that CAL binds to damaged DNA and effectively inhibits the cGAS-STING pathway-mediated inflammatory response. Furthermore, incorporating the cGAS-STING pathway inhibitor C176 into CAL greatly enhanced this inhibition to reduce inflammation and mitigate the lung tissue damage. These results suggest that regulation of immune homeostasis with multifunctional nanosheets may be a promising paradigm for managing ALI/ARDS in clinical settings.

Keywords: ALI/ARDS; Nanomedicine; Reactive oxygen species; SODase-like nanozyme; cGAS-STING.