Delivery of anti-microRNA-21 by lung-targeted liposomes for pulmonary fibrosis treatment
Lingyue Yan, Yafei Su, Isaac Hsia, Ying Xu, Vui King Vincent–Chong, Wilfrido Mojica, Mukund Seshadri, Ruogang Zhao, Yun Wu
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disorder with a low survival rate. Pulmonary fibrosis is one of the complications of COVID-19 and has a high prevalence in COVID-19 patients. Currently, no effective therapies other than lung transplantation are available to cure IPF and post-COVID-19 pulmonary fibrosis. MicroRNAs are small non-coding RNAs that mediate the development and progression of pulmonary fibrosis, thus making them potent drug candidates for this serious disease. MicroRNA-21 (miR-21) promotes not only the differentiation of fibroblasts to myofibroblasts but also epithelial-mesenchymal transition, both of which have been proposed as fundamental processes in pulmonary fibrosis development. Delivery of anti-miR-21 to block the miR-21-associated fibrogenic pathways represents a promising therapy for pulmonary fibrosis. However, microRNA treatment is challenged by quick degradation of RNA in blood, poor cellular uptake, and off-target effects. To overcome these challenges, we developed a lung-targeted, cationic liposome formulation to encapsulate anti-miR-21, enhance its delivery efficiency, and improve the therapeutic efficacy. We optimized the liposome formulation and demonstrated the anti-fibrotic effects using both in vitro and in vivo lung fibrosis models. Our results showed that anti-miR-21 delivered by cationic liposomes suppressed myofibroblast differentiation, reduced the synthesis of extracellular matrix, and inhibited fibrosis progression.