Utilizing Leucine Zippers to Mediate Improved Carrier Accumulation and Retention at the Site of Myocardial Infarction

Ischemic heart disease is the leading cause of death worldwide. Patients often experience dysregulated wound healing and become at risk for long-term heart failure and poor cardiac function. While mesenchymal stem cells and their derived extracellular vesicles are potent mediators of cardiac repair, their therapeutic efficacy is often limited by invasive intramyocardial injections and a lack of accumulation and retention at the target site. Therefore, the ability to administer a therapeutic that is minimally invasive but remains functional and localized at the infarct site is desperately needed. In this dissertation, I present a novel approach using heterodimerizing proteins, leucine zippers, decorated on the surface of cells for the development of a drug depot that is composed of an in situ forming network of cells and vesicles. When intravenously injected in alternating doses, these cells crosslink to create a scaffold-free network that remain at the infarct site for an extended period of time. Through a layer-by layer- dosing strategy, the targetable surface area is greatly increased. Furthermore, this methodology has been extended to extracellular vesicles for a nano-scaled and acellular approach for significantly enhanced retention and accumulation. Downstream effects on cardiac function and infarct size are also examined. Together, this work presents a new platform for improving vehicle delivery to the heart, non-invasively.