Bioinspired Inhalable Nanoparticles Combining Chinese Herbal Tetrandrine with Pirfenidone Overcome Idiopathic Pulmonary Fibrosis via Coordinated Collagen Modulation and Fibroblast Autophagy Regulation

Idiopathic pulmonary fibrosis (IPF), a lethal respiratory disease with few treatment options, occurs due to an excessive process of epithelial-mesenchymal transition (EMT) and abnormal accumulation of extracellular matrix (ECM), eventually leading to fibrotic scarring and destruction of alveolar structures. Here, a bioinspired inhalable nanocomplex (CCMφ@PTNPs) is reported for inhibiting the EMT progress and clearing the intrapulmonary ECM, thereby reversing established fibrotic foci in IPF. The nanocomplex consists of a PLGA core loaded with Chinese herbal tetrandrine (TET) and pirfenidone (PFD), and a macrophage cell membrane (Mφ) shell modified with collagenase type I (CLN) and collagen-targeting peptide (CBP). Following inhalation, CCMφ@PTNPs achieves precise abilities of targeting and degrading collagen barrier with the aid of CBP and CLN, ultimately achieving efficient penetration and drug delivery of fibrotic lesions in alveoli. The co-delivery of PFD and TET not only inhibited the transforming growth factor-β1(TGF-β1) pathway to achieve collagen modulation but also restored TGF-β1-induced impaired autophagy, which ultimately reduced local collagen production and accelerated clearance, thus synergistically enhancing the lung function of the bleomycin-induced mouse model. In summary, this study proposes a novel inhalation drug delivery strategy for the treatment of IPF.