This study aimed to elucidate the impact of quercetin (Que)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PLGA-Que) on hypoxia/reoxygenation (H/R)-induced cardiomyocyte (CM) injury and its mechanism. PLGA-Que was first prepared, and H/R CMs were intervened with either PLGA-Que
or free Que. The results showed that both PLGA-Que and free Que could enhance H/R CM viability, inhibit apoptosis, and lower the oxidative stress response. However, PLGA-Que was more protective of H/R CMs than free Que. Subsequently, noticeably enhanced viability and reduced apoptosis of H/R
CMs were determined after miR-499-5p or miR-375 up-regulation. Lastly, the inhibitor sequences of either miR-499-5p or miR-375 were transfected into PLGAQue-treated H/R CMs. The results showed that both sequences reversed the enhancement of viability and inhibition of apoptosis of H/R CMs
intervened by PLGA-Que. Thus, PLGA-Que can treat H/R-induced CM injury by up-regulating miR-499-5p and miR-375.