Maximizing Therapeutic Accumulation and Retention for Enhanced Cardiac Repair

PROJECT SUMMARY Ischemic heart disease and its complications are the primary cause of death in industrialized nations. Following myocardial infarction (MI), ~20-30% of patients develop heart failure, primarily due to loss of contractility through cardiomyocyte death, inflammation, and formation of scar tissue. Despite intensive research efforts, outcomes from new regenerative therapies for MI - such as those utilizing stem cells - have been disappointing to date. However, there is now compelling evidence that mesenchymal stem cells (MSCs) exert their cardio-reparative effects through the secretion of extracellular vesicles (EVs), whose intrinsic biological properties make them ide- al candidates for off-the-shelf therapies for ischemic heart disease. Despite a large body of research demon- strating the tissue-regenerative effects of EVs, their efficient delivery to injured myocardium has been hampered by three significant challenges: 1) injected EVs tend to diffuse quickly; 2) EVs and other carriers are not retained long-term in the heart; and 3) local intramyocardial injection is highly invasive. Systemic injection is safer but fails to deliver a sufficient dosage to the heart. Despite significant efforts to develop targeted delivery methods, there have been no substantive breakthroughs in addressing these challenges. The main objective of the proposal is to develop a novel delivery strategy that significantly improves EV accumulation and substantially prolongs cardiac retention in the injured heart. The specific aims of the study are as follows: (1) Synthesize and optimize EV formulations and dosing regimens and evaluate their biodistribution, biocompatibility, toxicity, and immunogenicity using a mouse model of MI. Furthermore, we will assess EV interactions with cells. (2) Investigate the capability of the optimized EV formulations to facilitate cardiac repair and explore the underlying mechanisms of action in a mouse model of MI. (3) Assess the effectiveness of EVs in mediating cardiac repair in a swine model of MI. These studies will pave the way for developing off-the-shelf EV therapies that can be administered non- invasively, offering effective treatment options for post-MI care without requiring invasive, open-chest surgery. This study will establish the critical design parameters of a first-in-class, non-invasive delivery and treatment strategy achieved through controlled in situ crosslinking. Importantly, our approach can be applied to different ligands and carrier systems (i.e., micro- and nanoparticles) for enhanced accumulation and retention, not only at infarct sites, but also other diseases.