pH-responsive PLGA nanoparticles enable sustained curcumin release and preserve mitochondrial bioenergetics in cardiomyocytes

The therapeutic potential of curcumin is severely limited by two intrinsic liabilities: a narrow therapeutic index caused by dose-dependent cytotoxicity and a short intracellular half-life that restricts bioactivity. Here, we present a nanoparticle-based strategy to overcome these challenges using poly(lactic-co-glycolic acid) (PLGA) nanoparticles engineered for pH-responsive, sustained release of curcumin. The formulation exhibited a hydrodynamic diameter of ~231 nm, high encapsulation efficiency, and accelerated release under acidic conditions. In a primary cardiomyocyte hypoxia-reoxygenation model, free curcumin displayed toxicity at concentrations above 5 µg/ml and failed to restore mitochondrial respiration. In contrast, PLGA–curcumin nanoparticles were non-toxic at 10 µg/ml and provided significant functional protection, enhancing cardiomyocyte contractility and uniquely rescuing mitochondrial bioenergetics, including basal respiration, ATP production, and spare respiratory capacity. These findings establish a direct mechanistic link between nanoparticle release kinetics and preservation of mitochondrial function, demonstrating how tailored delivery systems can transform the pharmacological profile of challenging molecules. This work provides a proof-of-concept for using pH-responsive PLGA nanoparticles as intracellular depots to unlock the therapeutic potential of curcumin and other unstable bioactive compounds.