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A high-performance hydrogel platform enabling dual anti-miR-21 and TGF-β1 delivery to improve arterial plaque stability and enhance therapeutic angiogenesis outcomes
Atherosclerosis is the primary cause of most cases of coronary artery disease, peripheral arterial disease, and many strokes. It is characte… (voir plus)rized 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. This research investigates a novel combination therapy utilizing anti-miR-21 and baculovirus expressing TGF-β1 gene for vascular tissue regeneration. A hemocompatible nanocomposite hydrogel with remarkable cellular adhesion profile was prepared by encapsulating anti-miR-21 and baculovirus expressing TGF-β1 gene in PLGA nanoparticles, followed by embedding them in a gelatin-genipin crosslinked nanocomposite hydrogel. Chorioallantoic membrane assay in chicken embryo and PTEN quantification study was used for angiogenesis. MTT assay followed by Annexin V-FITC/PI stained flowcytometry was used for HASMCs apoptosis study. The combination therapy demonstrates synergistic effects through dual mechanisms: promoting neo-vascularization via selective endothelial cell proliferation while inducing arterial smooth muscle cell apoptosis (22.27 ± 1.2%) 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.
A novel combination therapy of anti miR-21 and baculoviral TGFβ1 Gene via PLGA-gelatin-genipin nanocomposite hydrogel for arterial plaque stabilization and angiogenesis
One of the major challenges in vascular tissue regeneration is effective wound healing that can be resolved by an innovative targeted nanosh… (voir plus)uttle that delivers growth factors to blood vessels. This study investigates the production and efficacy of transforming growth factor-β1 (TGFβ1) gene delivery using poly(lactic- co -glycolic acid) (PLGA) baculovirus (BV) nanoshuttles (NSs). They exhibited an encapsulation efficiency of 86.23% ± 0.65% and a negative zeta potential of −29.57 ± 1.27 mV. In vitro studies in human umbilical vein endothelial cells (HUVECs) revealed that a 12 h incubation period optimized virus transduction. The safety and superior intracellular uptake of NSs and BVs in HUVECs were observed. The NSs carrying 100 and 400 MOI exhibited the highest cell proliferation rates in HUVECs. These sustained-release NSs significantly improved vascular cell migration and wound closure compared to free TGFβ1 carrying BV and can be a groundbreaking find in regenerative medicine, cardiovascular diseases, and chronic ulcer conditions.