Study on mannose-modified panax notoginseng polysaccharide self-assembled micelles to reduce idiopathic pulmonary fibrosis in mice

Idiopathic pulmonary fibrosis (IPF) is a life-threatening respiratory disease characterized by excessive proliferation of myofibroblasts and abnormal accumulation of extracellular matrix. At present, the treatment is limited. M2 macrophages play a key role in the pathogenesis of IPF. M2 macrophages are the main source of pro-fibrotic cytokine TGF-β1, which drives the progression of IPF by inducing epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transition (FMT), and highly express mannose (Man) specific surface receptors. This feature provides an important target basis for us to design targeted drug delivery systems. Emodin (Emo) is a potential anti-fibrosis drug, but its poor water solubility and low bioavailability are limited in clinical practice. Therefore, we constructed a self-assembling M2-targeting micellar (Man-Sa-Pnp-Emo@Ms) to target M2-type macrophages and inhibit the secretion of TGF-β1, blocking the core pathological process of pulmonary fibrosis. Cellular uptake, cytotoxicity, and anti-fibrotic effects (inhibition of fibroblast proliferation, invasion, and metastasis) were evaluated in vitro , and their targeting and anti-fibrotic effects were verified by in vivo imaging and histological staining (HE, Masson, immunofluorescence). The results showed that Man-Sa-Pnp-Emo@Ms had a homogeneous spherical structure, which improved the solubility of Emo and reduced the release of M2-type macrophage-derived TGF-β1. It inhibited FMT transformation and extracellular matrix accumulation (ECM) and exerted anti-fibrotic effects without damaging tissue-resident macrophages in vitro and in a bleomycin-induced mouse model. This work provides a novel nanodelivery strategy for the precision treatment of idiopathic pulmonary fibrosis.