Collagenase‐Coated Polymeric Drug/siRNA Nanoparticles Overcome ECM and Regulate Metabolic Reprogramming of Fibroblasts for Alleviating Pulmonary Fibrosis

ABSTRACT Pulmonary fibrosis (PF) is a progressive lung disease characterized by abnormal extracellular matrix (ECM) accumulation, leading to respiratory dysfunction and eventual respiratory failure. The pathogenesis involves fibroblast migration, proliferation, and activation via the CXCL12/CXCR4 axis, resulting in collagen deposition and ECM accumulation. Additionally, this axis drives epithelial‐mesenchymal transition (EMT) and angiogenesis. Under hypoxic conditions induced by ECM accumulation, pyruvate dehydrogenase kinase 1 (PDK1) further promotes fibroblasts differentiation into myofibroblasts by enhancing metabolic reprogramming towards glycolysis. To target these multifaceted pathological processes, a collagenase‐coated polymeric drug/siRNA delivery system is engineered. This system comprises PPLFazo, hypoxia‐responsive polymer of plerixafor (CXCR4 inhibitor), loaded with PDK1 siRNA (siPDK1) and encapsulated by collagenase‐conjugated polyglutamic acid. Upon inhalation, the collagenase degrades ECM barrier, facilitating PPLFazo/siPDK1 recognition and endocytosis by fibroblasts. In the hypoxic microenvironment, both plerixafor monomers and siPDK1 are released, exerting their targeted therapeutic effects. Pharmacodynamic evaluations in murine PF models demonstrated that PPLFazo/siPDK1@G‐CLG reduced myofibroblast accumulation, decreased collagen deposition, and attenuated abnormal fibrotic tissue growth in the lungs. These findings collectively indicate substantial amelioration of PF. By simultaneously targeting multiple pathological pathways, this system offers a novel strategy to combat this challenging disease, potentially improving patient outcomes.