Inhaled biomimetic nanoparticles enhance pulmonary delivery of tetrandrine and pirfenidone for the treatment of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease marked by epithelial-mesenchymal transition (EMT) and overactivation of the transforming growth factor-β (TGF-β) signaling pathway, leading to Collagen accumulation and macrophage infiltration in the lungs. Here, a bioinspired inhalable nanoplatform (PCMΦ@PPT) was designed and prepared for delivering therapy agents by penetrating the excessive physiological barrier deposited in the lesions and reversing established fibrotic foci in IPF. The nanoplatform was composed of two components: a pirfenidone (PFD) and tetrandrine (TET) co-loaded poly(lactic-co-glycolic acid) (PLGA) core (PPT), as well as a collagen-binding peptide and collagenase functionalized macrophage membrane (PCMΦ) shell. Following inhalation, PCMΦ@PPT has been shown to possess the capacity to target and penetrate the dense Collagen barrier with the assistance of functional groups present on PCMΦ. The coating of PCMΦ enables PCMΦ@PPT to evade phagocytosis by macrophages that accumulate at the site of lesions. Meanwhile, the precise co-delivery of PFD and TET to the lesion site not only blocks the TGF-β signaling pathway but also promotes the recovery of damaged Autophagy in fibroblasts, thereby alleviating the progression of IPF and partially improved lung function parameters of mice. In summary, this study proposes a novel nano-inhalation formulation for the treatment of IPF. STATEMENT OF SIGNIFICANCE: The biomimetic nanoparticle PCMΦ@PPT was designed to recognize and degrade overexpressed extracellular matrix proteins. It is composed of two components: a poly(lactic-co-glycolic acid) core co-loaded with pirfenidone (PFD) and tetrandrine (TET), as well as a collagen-binding peptide and collagenase-functionalized macrophage membrane shell (PCMΦ). Following inhalation, PCMΦ@PPT has been shown to target and penetrate the dense Collagen barrier while evading phagocytosis by macrophages, promoting drug retention in the focus. Finally, co-delivery of PFD and TET blocks the TGF-β signaling pathway, promoting recovery of damaged Autophagy in fibroblasts and alleviating IPF progression and restoring lung function.

Bioinspired inhalable nanoplatform; Biomimetic membrane; Collagen barrier penetration; Idiopathic pulmonary fibrosis.