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

Area of Science:

• Biomedical Engineering
• Nanomedicine
• Oral Pathology

Background:

• Oral submucous fibrosis (OSF) is a complex fibrotic disorder involving immune dysregulation, fibroblast activation, and disrupted vascular homeostasis.
• Simultaneously addressing these interconnected pathological axes in OSF presents a significant therapeutic challenge.

Purpose of the Study:

• To develop and evaluate a multifunctional nucleic acid nanomedicine for synergistic treatment of OSF.
• To investigate the potential of co-delivering anti-TGF-β siRNA and a proangiogenic aptamer for OSF microenvironment remodeling.

Main Methods:

• Development of Apt02-tFNAs-siTGF-β (A-T-S), a nanomedicine using tetrahedral framework nucleic acids to co-deliver siTGF-β and Apt02.
• In vitro assessment of A-T-S internalization and modulation of inflammatory, fibrotic, and angiogenic pathways in relevant cell types.
• Transcriptomic analysis to elucidate pathway reprogramming.
• In vivo evaluation in a rat OSF model, assessing collagen deposition, fibrotic signaling, inflammation, vascular changes, and organ toxicity.

Main Results:

• A-T-S demonstrated efficient cellular uptake and concurrent modulation of inflammatory, fibrotic, and angiogenic phenotypes in vitro.
• Transcriptomic profiling revealed coordinated reprogramming of key pathways involved in inflammation, fibrosis, and extracellular matrix remodeling.
• In vivo, A-T-S significantly reduced collagen deposition, profibrotic signaling, inflammatory infiltration, and vascular abnormalities in a rat OSF model, with no observed organ toxicity.

Conclusions:

• The multifunctional nanomedicine A-T-S synergistically remodels the OSF lesion microenvironment by targeting multiple pathological pathways.
• A-T-S represents a promising therapeutic strategy for oral submucous fibrosis and potentially other fibroinflammatory diseases.