A Lung-Targeted Self-Assembled Supramolecular nanofiber for Synergistic Therapy of Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options and high mortality rates. As an FDA-approved tyrosine kinase inhibitor, nintedanib (BIBF) effectively renders pulmonary fibrosis progression in the short term but offers limited clinical benefit. Drugs with synergistic effects may sustainably inhibit crucial signaling pathways, thereby enhancing anti-fibrotic activity. In preliminary research, we demonstrated that VS-6766, a surpassing RAF/MEK dual-inhibitor, possessed potential for allaying pulmonary fibrosis. Herein, we further investigated an underlying synergistic anti-fibrotic therapy combining BIBF with VS-6766. Supramolecular nanofiber, as filamentous microorganism biomimetic carriers, exhibited strong deposition and aggregation capabilities in the lungs. This specific morphology makes it a potential lung-targeted carrier. Hence, we designed a self-assembling peptide amphiphile (RPA) to co-deliver BIBF and VS-6766 (RPA@BV), which was based on the myofibroblast-targeted RDYH-58 sequence. After optimizing the drug-loading ratio, the supramolecular nanofiber RPA@BV exhibited ameliorated fibrosis suppression capacity. In vitro, the BIBF/VS-6766 combination demonstrated synergistic inhibition of fibroblast activation. In a bleomycin-induced murine IPF model, RPA@BV achieved rapid and prolonged lung accumulation post intravenous injection. After treatment, fibrotic pathology was significantly mitigated, as evidenced by reduced lung coefficient, decreased collagen deposition, and improved alveolar architecture on H&E and Masson Trichrome staining. Importantly, the formulation showed good biocompatibility in vivo. In conclusion, we developed a targeted co-delivery nanoplatform that synergistically enhanced the anti-fibrotic efficacy of BIBF and VS-6766, offering a promising strategy for IPF treatment.