Increased reactive oxygen species (ROS) production and elevated intracellular Ca2+ following cardiac ischemia-reperfusion injury are key mediators of cell death and the development of cardiac hypertrophy. The L-type Ca2+ channel is the main route for calcium influx in cardiac myocytes. Activation of the L-type Ca2+channel leads to a further increase in mitochondrial ROS production and metabolism. We have previously shown that the application of a peptide derived against the alpha-interacting domain of the L-type Ca2+ channel (AID) decreases myocardial injury post reperfusion. Herein, we examine the efficacy of simultaneous delivery of the AID peptide in combination with the potent antioxidants curcumin and resveratrol using multifunctional poly(glycidyl methacrylate) (PGMA) nanoparticles. We highlight that drug loading and dissolution are important parameters that have to be taken into account when designing novel combinatorial therapies following cardiac ischemia-reperfusion injury. In the case of resveratrol low loading capacity and fast release rates hinders its applicability as an effective candidate for simultaneous therapy. However in the case of curcumin, high loading capacity and sustained release rates enables its effective simultaneous delivery in combination with the AID peptide. Simultaneous delivery of both compounds allowed for effective attenuation of L-type Ca2+ channel-activated increases in superoxide ( assessed as changes in DHE fluorescence; Empty NP = 53.1±7.6%; NP-C-AID = 7.32±3.57%) and mitochondrial membrane potential (assessed as changes in JC-1 fluorescence; Empty NP = 19.8±2.8%; NP-C-AID=13.05±1.78%). We demonstrate in isolated rat hearts exposed to ischemia followed by reperfusion, that curcumin and the AID peptide in combination effectively reduce muscle damage, decrease oxidative stress and superoxide production in cardiac myocytes.