Heart failure following a myocardial infarction (MI) continues to be one of the leading causes of death. Immediately after MI, there is an initial inflammatory response with cardiomyocyte death and degradation of the extracellular matrix. This results in negative left ventricular (LV) remodeling leading to wall thinning, LV dilation, and depressed cardiac function. Several experimental approaches have been examined to inhibit this negative remodeling process. One promising direction is the use of injectable biomaterials, which can be used as stand-alone scaffolds to encourage endogenous repair or for delivering therapeutics such as cells, growth factors, or small molecules. Early intervention of MI has the potential to slow or inhibit the progression of negative LV remodeling. To date, most therapeutic delivery strategies have involved intramyocardial biomaterial injections, although translation to acute MI patients is unlikely given the increased risk of ventricular rupture immediately post-MI. One promising, minimally invasive strategy is the systemic injection of nanoparticles. However, many of the investigated systems lack long-term retention within the MI.