Targeted Delivery of Quercetin to the Brain via a Modified Polymeric Nanocarrier

ABSTRACT Quercetin (Qt) exhibits significant neuroprotective potential in Alzheimer's disease; however, its clinical translation is limited by poor solubility, low permeability, and inadequate brain bioavailability. In this study, a modified polymeric nanocarrier was developed to enhance Qt delivery to the brain. Polyethyleneimine (PEI) was conjugated with polyethylene glycol (PEG) and further functionalized with phenylalanine to reduce PEI‐associated toxicity and improve brain‐targeting efficiency. Successful polymer synthesis was confirmed by FT–IR spectroscopy, showing characteristic S─S bond formation at 790 cm − 1 , mass spectrometry (m/z 1087.3), and differential scanning calorimetry. Nanoparticles were optimized using a Quality by Design approach, yielding an experimental particle size of 161.4 ± 1.10 nm, zeta potential of 15.9 ± 2.5 mV, and high entrapment efficiencies of 84.21 % and 86.74 % for Qt‐PEI‐Np and Qt‐PEI‐PEG‐S‐S‐AA‐Np, respectively. SEM analysis revealed spherical nanoparticles with nanoscale surface roughness and good stability. In vitro release studies demonstrated sustained Qt release (98 % over 48 h). MTT assays and cytokine analysis (TNF‐α, IL‐1β, IL‐6) confirmed biocompatibility. Enhanced intestinal permeability, absence of hippocampal toxicity, and effective BBB transport further support the potential of this nanocarrier for targeted neurotherapeutic delivery.