Inhalable siRNA Targeting IL-11 Nanoparticles Significantly Inhibit Bleomycin-Induced Pulmonary Fibrosis

Abstract

For idiopathic pulmonary fibrosis (IPF), interleukin 11 (IL-11) is a pivotal cytokine that stimulates the transformation of fibroblasts into myofibroblasts, thus accelerating the progression of pulmonary fibrosis. Here, we develop an innovative inhalable small interfering RNA (siRNA) delivery system termed PEI-GBZA, which demonstrates impressive efficiency in loading siIL-11 targeting IL-11 (siIL-11) and substantially suppresses the differentiation of fibroblasts into myofibroblasts and epithelial-mesenchymal transition (EMT), reduces neutrophil and macrophage recruitment, and ultimately relieves the established fibrotic lesions in the IPF model. PEI-GBZA is prepared by modifying low-molecular-weight polyethylenimine (PEI) with 4-guanidinobenzoic acid (GBZA). The resulting PEI-GBZA may effectively encapsulate siIL-11 through a variety of interactions such as hydrophobic, hydrogen bonding, and electrostatic interactions, creating stable carrier/siIL-11 nanoparticles (PEI-GBZA/siIL-11 NPs). Upon inhalation, PEI-GBZA/siIL-11 NPs demonstrate effective retention in fibrotic lesions, leading to a marked mitigation of disease progression in a bleomycin-induced pulmonary fibrosis model. Impressively, this inhalation therapy exhibits negligible systemic toxicity. This work provides a universal and noninvasive RNA therapeutic delivery platform that holds significant promise for respiratory diseases. The potential for clinical application of this platform is substantial, offering a frontier for the treatment of IPF and potentially other pulmonary disorders.

Keywords: fibrotic lesions; inhaled administration; pulmonary fibrosis; respiratory diseases; siRNA delivery system.