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The production dysregulation of reactive oxygen species (ROS) and nitric oxide (NO) in ischemic tissues results in endothelial dysfunction, hyperinflammation and poor blood circulation. Here, we report a hybrid molecule, SA-10 with both NO donating and ROS scavenging abilities that demonstrated potent cytoprotection and tube formation activity in endothelial cells under H 2 O 2 -induced oxidative stress. SA-10 loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (SA-10 NPs) were delivered intramuscularly (IM) to two murine hindlimb ischemia models. In the acute mode ischemia/reperfusion (I/R), the muscle damage, hyperinflammation, and lung edema were significantly reduced 3 days post-dose while in the chronic ischemia model, significant improvement of blood perfusion and physical endurance was observed over 30 days (P < 0.05). Elderly patients with acute and chronic limb ischemia have limited options for surgical or endovascular interventions, so we anticipate that a product like SA-10 NPs has potential as one of the therapeutic alternatives to surgery. A novel hybrid nitric oxide donor/reactive oxygen species scavenger drug was successfully employed to treat two models of ischemia–reperfusion injury in mice. Packaged in PLGA nanoparticles, the hybrid molecule improved vascular health, reduced tissue death, and reduced inflammation following ischemic injuries in mouse hindlimbs. This novel therapeutic offers a much needed nonsurgical treatment option for patients in whom endovascular interventions are contraindicated. [Display omitted] [ABSTRACT FROM AUTHOR] more...