Cell Membrane Hybrid Liposome-Targeted Delivery of the Heat Shock Protein 90 C-Terminal Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) represents a grave challenge as it is characterized by high fatality rates and irreversible progression without effective clinical interventions available at present. Previous studies have demonstrated that inhibition of heat shock protein 90 (HSP90) by an N-terminal inhibitor disrupts its interaction with TGFβRII, leading to the instability of TGFβRII, thus blocking the role of transforming growth factor-β1 (TGF-β1), which could potentially ameliorate IPF symptoms. However, given that the broad spectrum of HSP90 N-terminal inhibitors may lead to unanticipated side effects, we hypothesize that C-terminal inhibitors of HSP90 can interfere with TGFβRII while minimizing adverse reactions. In this study, silybin, a C-terminal inhibitor of HSP90, was separated into monomers, and silybin A was screened for its superior efficacy against TGFβRII. To facilitate targeted therapy for treating IPF, a cell membrane hybrid liposome loaded with silybin A (Cm-A-Lip) was developed to deliver silybin A to lung fibroblasts through pulmonary drug delivery. A bleomycin-induced IPF mouse model was used to evaluate the efficacy of Cm-A-Lip. By examination of lung hydroxyproline content, wet weight, histology, and inflammatory factor expression, the results showed that pulmonary delivery of Cm-A-Lip could increase the drug retention time in lung tissue compared with intravenous injection. Furthermore, Cm-A-Lip exhibited superior antifibrotic activity relative to conventional liposmomes loaded with silybin A (A-Lip) while concurrently mitigating systemic inflammatory responses associated with silybin A administration, thus enhancing the overall safety profile.