Synergistic ROS scavenging and metabolic remodeling by MOF-engineered exosomes alleviates multiorgan fibrosis

ZIF-8 encapsulates urine-derived exosomes to enhance circulatory stability. • Polydopamine and specific antibodies enable precise multi-organ targeting. • The acidic pathological microenvironment triggers dynamic exosome release. • Exosomes and Cu-Cys nanozymes synergistically reverse multiorgan fibrosis. • This multifunctional platform provides a novel paradigm for clinical translation. Exosomes have emerged as an ideal therapeutic vehicle owing to their inherent biocompatibility, low immunogenicity, and capacity for efficient biomolecule delivery. Nevertheless, inherent limitations, such as poor stability, inadequate targeting specificity, and limited therapeutic mechanisms, significantly confine their clinical application. This study innovatively developed a multifunctional nanocomposite system (EXO@Cu-Cys@ZIF)PDA/Ab based on zeolitic imidazolate framework-8 (ZIF-8). This system achieved high-efficiency exosome encapsulation and pH-responsive controlled release through microporous confinement effects and markedly improved circulatory stability via polydopamine (PDA) coating. Organ-targeting capability was also enhanced through specific antibody modifications. By integrating the reactive oxygen species (ROS)-scavenging ability of Cu-Cys nanozymes with the gene regulatory function of exosomes, this platform can synergistically restore redox homeostasis, suppress key signaling pathways involved in fibrosis, and modulate lipid metabolism, thereby effectively reversing fibrosis in the lungs, liver, and kidneys. The system also addressed the bottleneck of traditional clinical application of exosomes through the three-dimensional synergy mechanism of “exosome protection and delivery system-nanozyme activity regulation-organ targeting module”. The system also provides a customized and universal solution for the simultaneous treatment of multiorgan-organ diseases. Schematic illustration of the preparation and in vivo/in vitro mechanism of (EXO@Cu-Cys@ZIF)PDA/Ab. Download: Download high-res image (142KB) Download: Download full-size image