Targeted Dual Small Interfering Ribonucleic Acid Delivery via Non‐Viral Polymeric Vectors for Pulmonary Fibrosis Therapy

Inhibiting the myofibroblast differentiation of lung‐resident mesenchymal stem cells (LR‐MSCs) is a promising yet challenging approach for pulmonary fibrosis (PF) therapy. Here, micelles formed by a graft copolymer of multiple PEGs modified branched polyethylenimine are used for delivering runt‐related transcription factor‐1 (RUNX1) small interfering RNA (siRNA) (siRUNX1) to the lung, aiming to inhibit the myofibroblast differentiation of LR‐MSCs. LR‐MSC targeting is achieved by functionalizing the micelle surface with an anti‐stem‐cell antigen‐1 antibody fragment (Fab′). Consequently, therapeutic benefits are obtained by successful suppression of myofibroblast differentiation of LR‐MSCs in bleomycin‐induced PF model mice treated with siRUNX1‐loaded micelles. Furthermore, an excellent synergistic effect of PF therapy is achieved for this micelle system loaded siRUNX1 and glioma‐associated oncogene homolog‐1 (Gli1) small interfering RNA (siGli1), a traditional anti‐PF siRNA of glioma‐associated oncogene homolog‐1. Hence, this work not only provides RUNX1 as a novel PF therapeutic target, but also as a promising dual siRNA‐loaded nanocarrier system for the therapy of PF. Nanocarriers loaded with siRNA enter lung‐resident mesenchymal stem cells (LR‐MSCs) by targeting the cellular surface receptor Sca1. Successful suppression of myofibroblast differentiation of LR‐MSCs is obtained by silencing the RUNX1 and Gli1 genes in an IPF mouse model administered with Fab′ (siRUNX1 + siGli1)‐loaded micelles.