Following myocardial infarction (MI), the accumulation of CD86-positive macrophages in the ischemic injury zone leads to secondary myocardial damage. Precise pharmacological intervention targeting this process remains challenging. This study engineered a nanotherapeutic delivery system with CD86-positive macrophage-specific targeting and ultrasound-responsive release capabilities. A folic acid (FA)-modified ultrasound-responsive gene/drug delivery system, assembled from DOTAP, DSPE-PEG2000-FA, cholesterol, and perfluorohexane (PFH)-termed FA-PNBs-was developed to codeliver small interfering RNA of STAT1 (siSTAT1) and the small-molecule nitro-oleic acid (OA-NO) into CD86-positive macrophages. Upon irradiation with low-intensity focused ultrasound, FA-PNBs release siSTAT1 and OA-NO at the ischemic injury zone. The results demonstrated the system's precise targeting and efficient delivery capabilities. The combined modulation of OA-NO and siSTAT1 optimizes the immune microenvironment in the infarcted region, alleviates ventricular remodeling, preserves cardiac function, and holds promise for clinical intervention strategies after MI.