Spatiotemporal reprogramming of cardiac lipid metabolism by platelet-engineered RNA therapy epigenetically modulate heart repair and regeneration

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. • Efficient intracellular delivery: MSNs facilitate transmembrane transport and protect siRNA from enzymatic degradation. • Intrinsic targeting: Platelets provide biocompatibility and homing to injured myocardium, enabling precise, non-invasive delivery of RNA therapeutics. • Precise Metabolic reprogram: siCD36@MSNs@Plt selectively modulates lipid metabolism and epigenetics for myocardial regeneration, but avoids lipotoxic stress and systemic imbalance. • Functional regeneration: Treatment enhances cardiomyocyte proliferation and restores cardiac function after ischemia–reperfusion injury. • Clinical scalability: The system is low-cost, rapidly assembled ex vivo, and compatible with standard intravenous infusion.