Local Delivery of Bcar3 siRNA by Nano-Self-Assembly for Treating Pulmonary Fibrosis via Blocking the Interaction of Macrophages and Fibroblasts

Background: Idiopathic pulmonary fibrosis (IPF) is a life-threatening progressive interstitial lung disease with limited therapeutic options, characterized by macrophage infiltration and fibroblast activation in response to chronic lung injury. Specifically, the interaction of macrophages and fibroblasts is critical for facilitating IPF progression. However, no valuable therapeutic strategy has been proposed to inhibit this crosstalk. Results In this study, we investigated the role of breast cancer anti-estrogen resistance 3 (Bcar3), an adaptor molecule in the mitogenic signaling pathway, in IPF pathogenesis. We found that Bcar3 expression was upregulated in the lung tissues of both IPF patients and fibrotic mice. Furthermore, Bcar3 facilitated macrophage activation and fibroblast differentiation induced by IL-4 and TGF-β1, respectively. Mechanistically, Bcar3 up-regulation depended on Stat6 in macrophages and TGFβR1/Smad3 in fibroblasts. Furthermore, Bcar3 enhanced IL-4/Stat6 and TGF-β/Smad3 signaling in macrophages and fibroblasts, respectively, establishing a reciprocal activation loop between these two cell types, thus accelerating lung fibrogenesis. Additionally, intratracheal administration of Bcar3 siRNA-loaded liposomes afforded a precise delivery of gene therapeutics to macrophages and fibroblasts in the lung, protecting mice against FITC or bleomycin-induced lung fibrosis, as well as in human precision-cut lung slices stimulated with TGF-β1. Conclusions Overall, our study not only highlights the critical role of Bcar3 in the interaction between macrophages and fibroblasts during the progression of pulmonary fibrosis but also demonstrates that strategies aimed at targeting Bcar3 could be considered a promising therapeutic strategy for managing IPF.