A novel combination therapy of anti miR-21 and baculoviral TGFβ1 Gene via PLGA-gelatin-genipin nanocomposite hydrogel for arterial plaque stabilization and angiogenesis

Atherosclerosis is the primary cause of most cases of coronary artery disease, peripheral arterial disease, and many strokes. It is characterized by pathological vascular smooth muscle cell hyperplasia. Current treatment regimens are associated with several adverse effects including hepatotoxicity, hemorrhagic complications, and non-selective cellular inhibition. Plaque stabilization and angiogenesis are critical for mitigating adverse cardiovascular outcomes. Stabilized plaques exhibit reduced vulnerability to rupture, thereby lowering the risk of thrombus formation, myocardial infarction, and ischemic stroke. Transforming Growth Factor Beta 1 (TGF-β1cells) is instrumental in promoting angiogenesis, facilitating the regrowth of endothelial cells, and contributing to the stabilization of atherosclerotic plaques. Anti-miRNA 21 can lead to plaque stabilization by decreasing inflammation and limiting the growth of smooth muscle cells while encouraging cell death, which helps prevent plaque rupture. PLGA nanoparticles can ensure high encapsulation and effective delivery of genes and viral vectors over time and can offer superior protection for their encapsulated contents, which is particularly valuable for delicate substances such as proteins and nucleic acids. This research investigates a novel combination therapy utilizing baculovirus expressing TGF-β1 gene and anti-miR-21, incorporated into gelatin-genipin polymeric nanocomposite hydrogels. The therapy demonstrates synergistic effects through dual mechanisms: promoting neo-vascularization via selective endothelial cell proliferation while inducing smooth muscle cell apoptosis to control extracellular matrix secretion and stabilize plaque. The therapeutic efficacy is evidenced by significant reduction in PTEN expression (251.1 ± 16 pg/ml compared to 375.2 ± 5.29 pg/ml in control) and enhanced angiogenic responses in the CAM assay, showing a 126.46 ± 16.62% increase in vessel length.