Platelet-engineered AAV silencing of myocardial CD36 reprograms fatty acid metabolism to promote cardiac regeneration in male mice

The adult heart has limited regenerative capacity after ischemic injury, and abnormal fatty acid metabolism contributes to this failure of repair. Strategies that reduce fatty acid oxidation can promote cardiomyocyte proliferation, but excessive suppression may disrupt lipid handling and worsen injury. Here we show that a platelet-engineered adeno-associated virus (AAV) delivery system enables targeted suppression of the fatty acid transporter CD36 and promotes cardiac repair after ischemia-reperfusion injury. By using platelets as injury-responsive carriers, the system preferentially accumulates in damaged myocardium, reduces neutralization by circulating antibodies, and enhances cardiac delivery of the therapeutic vector. In a male mouse model, CD36 knockdown reduces fatty acid utilization, reshapes cardiac lipid metabolism without causing overt lipid overload, increases cardiomyocyte cell-cycle activity, and improves cardiac structure and function. These findings establish a platelet-guided gene delivery strategy that links metabolic reprogramming to myocardial regeneration and suggest a promising approach for ischemic heart repair. Gene therapy for the injured heart is limited by poor targeting and neutralizing antibodies against viral vectors. Here, the authors show that platelets can ferry CD36-silencing AAV to damaged myocardium, reprogramming metabolism and restoring heart function in mice.