Myocardial infarction (MI) is a prominent manifestation of heart disease with very high mortality. Despite the great success of surgical and intravascular interventions and thrombolytic therapies, MI mortality remains high and a significant percentage of MI survivors suffer from heart failure. Thus, there is a strong need and large market for new drugs to further reduce mortality and to treat post-MI heart failure. Treatment of MI requires timely reopening of the blocked coronary artery and reperfusion of the ischemic tissue. However, reperfusion itself may induce myocardial ischemia/reperfusion (MI/R) injury, which increases cardiac damage and mortality. It was shown that inflammation, consequent vascular leakage and microvascular thrombosis all play critical roles in MI/R injury. Anti-platelet drugs are routinely used in acute MI patients, mainly for the prevention of secondary thromboses or stent thrombosis. As microvascular thrombosis is a key factor in MI/R injury, anti- platelet drugs, in theory, should be protective. However, although anti-platelet treatment improves MI outcome in general, the more potent and fast-onset intravenous anti-platelet drugs, when used on top of mild and slow- acting oral anti-platelet drugs, are not significantly more effective in improving MI outcome than oral anti- platelet drugs alone. As the increased potency of the current anti-platelet drugs is associated with increased adverse effect of causing vascular leakage and bleeding, which are also important factors in MI/R injury, we hypothesize that these adverse effects may limit the efficacy of anti-platelet drugs in treating MI/R injury. Based on our new concept (Gong et al Science 2010, Shen et al, Nature 2013) that G13-dependent outside-in signaling of the platelet integrin IIb3 (GPIIb-IIIa) is selectively important in occlusive thrombosis but not hemostasis, we designed a peptide inhibitor of the G13-integrin interaction, M3mP6, and a novel high-loading peptide nanoparticle (HLPN) formulation for in vivo intracellular peptide delivery. In proof-of-concept studies, we have demonstrated that M3mP6 HLPN potently inhibits occlusive intravascular thrombosis without causing bleeding. Importantly, M3mP6 also has anti-inflammatory effects mediated by inhibition of 2-G13 binding in leukocytes, thereby reducing neutrophil function. M3mP6 had a striking therapeutic effect in treating MI/R injury in a mouse model. Pilot toxicology studies carried out with M3mP6 HLPN showed no toxicity. Based on these exciting new data, we propose in this direct Phase II SBIR application to further develop this novel drug from the proof-of-concept stage to IND for the treatment MI/R injury and prevention of post-MI heart failure. Our specific aims are (1) to compare the effect of M3mP6 HLPN to current standard anti-platelet therapy as well as their additive effects in treating MI/R injury and preventing post-MI heart failure in animal models. (2) to further evaluate the adverse e...