Inhaled siRNA nanoparticles targeting IL11 inhibit lung fibrosis and improve pulmonary function post-bleomycin challenge

• Main Authors: Bai, X. (Author), Chen, Q. (Author), Gao, M. (Author), Ho, W. (Author), Li, Z. (Author), Xu, X. (Author), Zhang, X.-Q (Author), Zhao, G. (Author)
• Format: Article
• Language: English
• Published: NLM (Medline) 2022
• Online Access: View Fulltext in Publisher

 Interleukin-11 (IL-11) is a profibrotic cytokine essential for the differentiation of fibroblasts into collagen-secreting, actin alpha 2, smooth muscle-positive (ACTA2+) myofibroblasts, driving processes underlying the pathogenesis of idiopathic pulmonary fibrosis (IPF). Here, we developed an inhalable and mucus-penetrative nanoparticle (NP) system incorporating siRNA against IL11 (siIL11@PPGC NPs) and investigated therapeutic potential for the treatment of IPF. NPs are formulated through self-assembly of a biodegradable PLGA-PEG diblock copolymer and a self-created cationic lipid-like molecule G0-C14 to enable efficient transmucosal delivery of siIL11. Noninvasive aerosol inhalation hindered fibroblast differentiation and reduced ECM deposition via inhibition of ERK and SMAD2. Furthermore, siIL11@PPGC NPs significantly diminished fibrosis development and improved pulmonary function in a mouse model of bleomycin-induced pulmonary fibrosis without inducing systemic toxicity. This work presents a versatile NP platform for the locally inhaled delivery of siRNA therapeutics and exhibits promising clinical potential in the treatment of numerous respiratory diseases, including IPF.