Consumption of Endogenous Caspase‐3 Activates Molecular Theranostic Nanoplatform against Inflammation‐Induced Profibrotic Positive Feedback in Pulmonary Fibrosis

Abstract The limited and backward diagnostic approaches elicit high mortality associated with pulmonary fibrosis (PF) because they fail to identify injury phase of PF. Developing a precisely theranostic nanoplatform presents a promising shortcut to reverse PF. Herein, a specific molecular nanotheranostic (Casp‐GNMT), which is triggered by endogenous cysteinyl aspartate specific proteinase‐3 (caspase‐3), boosts antifibrotic efficacy through bioimaging synergistic with chemotherapy at molecular level, facilitating by ionizable lipid and reactive oxygen species sensitive lipid for precise and manageable therapy. The activation of molecular imaging probe (pCY‐pairs) by consumption of endogenous caspase‐3 initiates fluorescence resonance energy transfer‐guided theranostic pattern, aiming to restore mitochondrial dysfunction‐induced oxidative stress and inflammatory responses in alveolar epithelial cells II (AECs II). This process sequentially resists the expression of interleukin‐1β and vascular endothelial growth factor receptor through combined with nintedanib, further suppressing abnormal injury of AECs II and persistent migration and proliferation of inflammatory cells. Especially, the homeostasis of injured AECs II diminishes excessive accumulation of transforming growth factor‐β to restrain myofibroblasts proliferation and collagen deposition, thereby amplifying the possibility of reversing PF. This theranostic nanoplatform is proposed to provide a prompt and exact approach to enhance diagnostic authenticity and treating efficiency through harnessing endogenous indicator for PF reversal.