Molecular Engineering of Metallic Nanoparticle Using Natural Flavonoids: From Synthesis to Biological Evaluation

Parkinson's disease (PD) is a progressive neurodegenerative disorder driven by oxidative stress, neuroinflammation, and mitochondrial dysfunction. Although flavonoids such as luteolin and fisetin exhibit strong antioxidant and neuroprotective properties, their therapeutic utility is limited by poor solubility, stability, and bioavailability. The present study aimed to synthesize, characterize, and evaluate the safety and antioxidant potential of luteolinand fisetin-loaded zinc oxide nanoparticles (LF-ZnONPs) as a nanomedicine-based strategy for neurodegenerative disorders.

LF-ZnONPs were synthesized using a chemical method and characterized by UV- visible spectroscopy, Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), and thermogravimetric analysis (TGA). Drug loading, encapsulation efficiency, in vitro drug release, and antioxidant activity (DPPH assay) were assessed. Acute and sub-acute oral toxicity studies were conducted in male Wistar rats following OECD guidelines, supported by hematological, biochemical, and histopathological analyses.

LF-ZnONPs exhibited spherical morphology with particle sizes of 50-100 nm and high crystallinity. FTIR and TGA confirmed stable flavonoid incorporation. The formulation demonstrated high encapsulation efficiency (90.36%) and sustained drug release, with 57.88% cumulative release within 40 minutes. Significant, concentration-dependent antioxidant activity was observed. Acute toxicity testing revealed an LD50 of approximately 1667 mg/kg, indicating low acute toxicity. Sub-acute studies showed mild, dose-dependent biochemical and histopathological changes at higher doses, while lower doses remained within physiological safety limits.

Encapsulation of luteolin and fisetin within ZnO nanoparticles enhanced stability and functional performance while maintaining an acceptable safety profile. The findings are consistent with existing literature supporting flavonoid-based nanocarriers for oxidative stress- mediated neurodegeneration.

LF-ZnONPs represent a safe and promising nanocarrier system with potential application in the management of Parkinson's disease, warranting further mechanistic and diseasespecific efficacy studies.