Ischemic heart disease remains a leading global cause of morbidity and mortality, driven by the irreversible loss of cardiomyocytes (CMs) and their limited regenerative capacity. Suppression of fatty acid oxidation (FAO) has shown potential to restore CMs proliferation, but global inhibition of mitochondrial FAO usually results in lipid accumulation and metabolic stress. Targeting fatty acid uptake via CD36, a key transmembrane transporter, offers a more selective strategy to constrain FAO while minimizing lipotoxicity. Here, we report a bioresponsive siRNA delivery system composed of platelet-encapsulated mesoporous silica nanoparticles (Plt-MSNs) loaded with CD36-targeting siRNA. Exploiting the open canalicular system (OCS), platelets internalize siRNA cargo and enable specific delivery via their innate homing ability to sites of myocardial injury. In a murine ischemia-reperfusion model, Plt-MSNs achieved targeted delivery and stimulus-responsive release of siCD36, effectively reprogrammed CMs lipid metabolism, remodeled the epigenetic landscape, that eventually promoted proliferation without lipid toxicity. This approach offers a platform for regenerative gene therapy through metabolic-epigenetic reprogramming.
