An Inhalable Enzyme‐Peptide Nanogel for Enhanced Pulmonary Fibrosis Therapy

ABSTRACT Pulmonary fibrosis is driven by progressive extracellular‐matrix accumulation and persistent profibrotic signalling, yet current therapies primarily slow functional decline and rarely remodel established scar. Here we report an inhalable enzyme–peptide nanogel (COL@OSA‐KK8) that targets a central matrix–macrophage amplification loop by combining local collagen degradation with inhibition of macrophage‐mediated activation of transforming growth factor β1 (TGF‐β1). The nanogel is formed by chemically crosslinking collagenase with oxidized sodium alginate and functionalized with a CD36‐targeting peptide (KK8), yielding a nebulization‐compatible formulation for distal lung delivery. COL@OSA‐KK8 degrades pathological type I collagen and interferes with thrombospondin 1 (TSP‐1)/CD36‐dependent activation of latent TGF‐β1 in alveolar macrophages, thereby interrupting a feed‐forward matrix–macrophage profibrotic circuit. The inhaled COL@OSA‐KK8 mitigates fibrotic remodelling, reduces lung collagen burden and hydroxyproline content, lowers active TGF‐β1 levels, and improves survival. These findings establish nanogel‐enabled inhaled enzyme delivery as a robust strategy for pulmonary fibrosis therapy.