A nanosystem targeting tissue inhibitor of metalloproteinase-1 for continuous spatiotemporal idiopathic pulmonary fibrosis therapy

Idiopathic pulmonary fibrosis (IPF), a progressive, life-threatening disease marked by excessive collagen deposition, severe tissue injury, and dysregulated oxidative stress, poses a major threat to human health. Despite clinical advances, current therapies have limited anti-fibrotic efficacy. Here we show a reactive oxygen species (ROS)-responsive nanosystem targeting tissue inhibitor of metalloproteinase-1 (TIMP-1) for spatiotemporally precise IPF treatment. Anti-TIMP-1 antibodies (aT) are conjugated to mesenchymal stem cell-derived exosomes (Mexo) via ROS-cleavable phenylboronic acid ester linkers (cl), yielding Mexo-cl-aT. Following intratracheal administration, cl linkers are selectively cleaved by elevated ROS in the IPF microenvironment, enabling ROS scavenging while releasing Mexo and aT to mediate tissue repair and collagen degradation, respectively. We demonstrate that a single dose of Mexo-cl-aT exerts robust therapeutic efficacy against IPF in a bleomycin-induced mouse model of advanced-stage fibrosis, thereby validating this nanosystem as a safe and efficient candidate for next-generation IPF therapies.