Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in developed nations, and heart disease is predicted to remain the leading killer for the foreseeable future.Acute myocardial infarctions (MI)—1.2 million annually occurring in the U.S.alone—are the major CVD subgroup.Blood supply to the heart is occluded during MI, and the ensuing hypoxic and anemic hypoxia triggers deleterious responses within the affected tissue, affecting cardiomyocyte (CM) and endothelial cell function and viability.Largely non-regenerative, the pressure overload leads to non-contractile scar formation and the infarcted heart undergoes a degenerative process toward heart failure.Beyond immediate treatments to restore coronary blood flow, the medical community lacks therapeutic strategies to effectively intervene in the long-term progression of cardiac dysfunction.The first section of this thesis examines two synthetic drug delivery vehicles to mitigate myocyte cell death and enhance vasculogenesis.The second part focuses on amplifying endogenous cardiac signals to treat the heart, and elucidating clues from said signals for bio-inspired therapeutics.Although many drugs exist that may aid ischemic myocytes, intracellular delivery of such drugs remains a hurdle, owing to the non-phogocytic nature of myocytes.Here,we describe a novel drug delivery system that relies on surface decoration with N-acetylglucosamine (GIcNAc) to induce internalization.We tested the ligand with an acid-degradable polymeric nanoparticle poly(cyclohexane-1,4-diyl acetone dimethylene ketal)(PCADK) encapsulating an anti-apoptotic small molecule, SB239063.The vehicle mitigated the effects of MI in a rat model: it reduced cell death in vivo and improved cardiac function.We also developed a dendrimeric delivery vehicle that exhibited region-selective decoration with the internalizing tripeptide arginine-glycine-aspartic acid (RGD)and loaded it with the angiogenic microRNA, miR-126.This vehicle promoted vasculogenesis in vitro and may prove useful in enhancing blood flow within the infarcted cardiac zone.A small population of stem cells resides in the heart, termed cardiac progenitor cells (CPCs).We collected the exosomes secreted in various conditions and treated cardiac endothelial and fibroblast cell lines with concentrated doses of the exosomes.The hypoxic exosomes enhanced tube formation of endothelial cells and attenuated cytokine stimulation of fibroblasts, indicating that they may restore blood flow to the infarct and mitigate excessive scar formation in the heart.We characterized the miR signature that CPCs release in response to hypoxic conditions and found several to be upregulated in secreted exosomes.Statistical analysis revealed clusters of co-varying miRs and predicted their physiological response, laying groundwork for development of rationally bio-inspired therapeutics.