Inhalable Nanomedicine Targeting Macrophages for Modulation of the STING Pathway in Pulmonary Fibrosis Therapy

Recent evidence suggests that aberrant activation of the stimulator of interferon genes (STING) pathway in macrophages plays a critical role in driving inflammatory and fibrotic responses. To investigate this, we developed an inhalable lipid nanoparticle (LNP) platform encapsulating Cas9 mRNA and a sgRNA targeting Sting (mCas9/gSting@DOPS LNPs), enabling selective disruption of STING signaling in lung macrophages.

Using a bleomycin-induced mouse model of pulmonary fibrosis, we performed bulk RNA sequencing on whole-lung tissues from healthy controls, bleomycin-challenged mice, and mCas9/gSting@DOPS LNP–treated mice. Transcriptomic profiling revealed extensive remodeling of the fibrotic lung environment, including suppression of type I interferon and chemokine signaling, restoration of immune homeostasis, and enrichment of pathways associated with tissue repair.