A Multifunctional Nucleic Acid Nanomedicine Coregulates Angiogenesis and Fibrosis to Treat Oral Submucous Fibrosis

Oral submucous fibrosis (OSF) is a chronic progressive oral fibrotic disorder characterized by dysregulated immune inflammation, fibroblast activation, and vascular homeostasis disruption, yet synchronously regulating these axes remains challenging. We developed a multifunctional nucleic acid nanomedicine, Apt02-tFNAs-siTGF-β (A-T-S), in which tetrahedral framework nucleic acids co-deliver siRNA against TGF-β (siTGF-β) and the proangiogenic aptamer Apt02, enabling programmable integration and stable delivery. A-T-S was efficiently internalized by macrophages, human oral mucosal fibroblasts, and endothelial cells and concurrently modulated inflammatory phenotypes, fibrotic programs, and angiogenesis-related features in vitro. Transcriptomic profiling revealed coordinated reprogramming of pathways involved in inflammation, fibrosis, and extracellular matrix remodeling. In a rat OSF model, A-T-S reduced collagen deposition and profibrotic signaling while mitigating inflammatory infiltration and vascular abnormalities, without evident toxicity in major organs. These findings indicate that A-T-S can synergistically remodel the OSF lesion microenvironment and represents a promising strategy for OSF and other fibroinflammatory diseases.