Cardiomyocyte Membrane‐Camouflaged Spinach Nano‐Thylakoids Enhance Myocardial Energy Metabolism and Ameliorate Heart Failure

BACKGROUND: Energy deficiency and mitochondrial dysfunction are key features of heart failure (HF), while current therapies only indirectly improve cardiac metabolism. We developed a biomimetic photoactivatable nanoplatform, cardiomyocyte membrane-camouflaged photosynthetic nano-thylakoids (MM-NTU), to enhance myocardial bioenergetics. METHODS AND RESULTS: Nano-thylakoids were isolated from spinach chloroplasts, downsized, and coated with cardiomyocyte membranes to improve cardiac association and retention. In transverse aortic constriction (TAC) rats, intramyocardial MM-NTU administration combined with red-light activation improved systolic function, reduced fibrosis, and attenuated ventricular remodeling. In angiotensin II-injured cardiomyocytes, MM-NTU stabilized mitochondrial membrane potential, increased ATP production, and suppressed hypertrophic and profibrotic markers. Multi-omics analyses revealed restoration of glucose-related metabolites and mitochondrial energy intermediates, reduced oxidative stress, and improved bioenergetic efficiency. MM-NTU also modulated AMPK-related signaling and altered Pck1 and Adipoq expression, consistent with enhanced glucose utilization. Biodistribution and histological analyses showed favorable biocompatibility without evident major-organ toxicity. CONCLUSIONS: MM-NTU enhances ATP generation, glucose utilization, and mitochondrial energy metabolism, thereby improving myocardial bioenergetics and cardiac function under pressure overload.