Cardiac‐Targeted Quercetin‐Loaded PLGA Nanoparticles Attenuate Doxorubicin‐Induced Cardiotoxicity via Nrf2/HO‐1 Pathway Activation in Mice

ABSTRACT Doxorubicin (DOX) is a widely used chemotherapeutic agent, but its clinical application is limited by dose‐dependent cardiotoxicity linked to oxidative stress, mitochondrial dysfunction, and apoptosis. Quercetin (QU), a natural flavonoid with potent antioxidant properties, provides cardioprotection but exhibits poor bioavailability. This study aimed to enhance the cardioprotective efficacy of QU using poly (lactic‐co‐glycolic acid) (PLGA) nanoparticles functionalized with a cardiac‐targeting peptide. QU‐loaded PLGA nanoparticles (NQP) were synthesized via a microfluidic method and conjugated with the CSTSMLKAC peptide. Physicochemical properties, release behavior, and morphology were characterized. Male mice ( n = 72; nine groups) were used to study DOX‐induced cardiotoxicity and different treatments with free QU or NQP (10–50 mg/kg). Oxidative stress markers, mitochondrial function, serum biomarkers, histopathology, and cardiac Nrf2/HO‐1 expression were evaluated. Optimized NQPs (150.7 ± 0.98 nm, −27.85 ± 0.23 mV, EE = 64.01 ± 1.47%) showed biphasic release with enhanced drug liberation at pH 5.5. DOX significantly decreased superoxide dismutase (SOD), glutathione (GSH), and mitochondrial viability while elevated lipid peroxidation (LPO), reactive oxygen species (ROS), and protein carbonyl (PC) when compared to the control group. NQP25 and NQP50 significantly restored antioxidant defenses, improved mitochondrial membrane potential (MMP), reduced oxidative damage, and upregulated Nrf2/HO‐1 gene expression compared to DOX and free QU groups. Serum troponin I and CK‐MB levels were significantly decreased in the NQP50 group, with cardiac histopathology damage and inflammation also being reduced by NQPs. PLGA‐functionalized nanoparticles enhanced the cardioprotective effects of QU against DOX‐induced injury by boosting antioxidant defenses, activating the Nrf2/HO‐1 signaling pathway, maintaining mitochondrial function, and preserving myocardiocyte integrity. This targeted nanoplatform shows strong potential for reducing cardiotoxicity associated with chemotherapy.