(4ph) Siyang Wang

Atherosclerotic vascular disease and downstream tissue ischemia such as heart attacks and strokes remain the leading cause of morbidity and mortality in the United States and globally. Atherosclerosis is the narrowing or hardening of arteries ascribed to the buildup of fatty plaque in the inner lining of arteries. Although pharmacological treatments of atherosclerosis primarily focus on systemic risk factors, which center on lowering blood cholesterol levels, nucleotide-based therapies have emerged to revolutionize future medical practices, such as recently developed mRNA-based COVID-19 vaccines. However, delivering therapeutic nucleotides remains challenging due to rapid in vivo degradation, poor cellular uptake in target cells, and unwanted side effects in non-target tissues. My postdoctoral study with Profs. Matt Tirrell and Yun Fang focuses on engineering nanocarriers to achieve targeted delivery of therapeutic microRNA to treat atherosclerosis. The target of interest is vascular smooth muscle cells (VSMC), a major cell type that participates in all stages of atherosclerosis development and transdifferentiates into most cells that make up atherosclerotic plaques. We engineered polyelectrolyte complex micelles (PCMs) displaying a VSMC-targeted peptide and encapsulating micro-RNA-145 (miR-145), which directs VSMC fate and regulates VSMC phenotypes. PCMs self-assemble through electrostatic interactions between positively charged lysines in poly(ethylene glycol)-b-poly(L-lysine) copolymers and negatively charged miR-145. The PCMs we have developed can successfully deliver miR-145 towards VSMCs as well as significantly reduce the rate of progressive increase in plaque area. My doctoral research in Prof. Marek Urban’s group focused on developing novel autonomous self-healing and stimuli-responsive polymeric materials ranging from acrylic-based fluorinated copolymers and polyionic liquid copolymers to covalent adaptable networks. In-depth studies were conducted to understand self- healing mechanisms using spectroscopic tools, thermo-mechanical analysis, and molecular dynamic simulations. Combining my postdoc and doctoral research experiences formulated my future interests in developing biomimetic flow-sensitive and responsive materials to aid the treatment of vascular complications. The development of atherosclerosis prefers the arterial sites of curvature, branching and bifurcation where disturbed blood flow is prevalent. Low and oscillatory shear stress generated by disturbed blood flow induces endothelial dysfunction, which initiates the development of atherosclerosis. In contrast, the arteries exposed to unidirectional flow largely resist atherosclerosis. The objectives of my future research are driven by the hypothesis that the mitigation of atherosclerosis can be achieved by controlling/interfering with local blood flow patterns with the help of flow-sensitive and responsive biomaterials. These smart materials will actively respond to undesired flow and redirect it into a favorable flow pattern. With built-in actuators, the reorientation can also trigger localized release of nanomedicine or small molecule drugs if needed.