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

ABSTRACT 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.