Design, Optimization, and Experimental Evaluation of Quercetin-Loaded Solid Lipid Nanoparticles for Neuroprotection: Pharmacognostic Characterization, Blood–Brain Barrier Targeting, Behavioral Pharmacology, Oxidative Stress Biomarkers, and Molecular Mecha

Abstract

The present study was designed to develop and experimentally evaluate quercetin-loaded solid lipid nanoparticles (Q-SLNs) as a potential nanocarrier for enhanced neuroprotection. Quercetin was selected because of its well-established antioxidant and anti-inflammatory properties, although its therapeutic application is limited by poor aqueous solubility and bioavailability. The selected plant material was subjected to pharmacognostic and phytochemical evaluation, followed by quercetin identification and quantification. Q-SLNs were prepared using a lipid-based nanoparticle technique and optimized for particle size, polydispersity index, zeta potential, entrapment efficiency, drug loading, and drug release. The optimized formulation showed nanoscale particle size, high quercetin entrapment, sustained drug release, and favorable morphological and structural characteristics. The formulation also demonstrated improved BBB-oriented transport and cellular uptake compared with free quercetin. In the experimental neuropharmacological evaluation, Q-SLNs produced greater improvement in learning, memory, and behavioral performance than free quercetin. Treatment also reduced oxidative stress, as evidenced by decreased MDA and restoration of GSH, SOD, CAT, and GPx levels, along with suppression of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6. Molecular investigations indicated enhanced Nrf2/HO-1 and PI3K/Akt signaling, suppression of NF-κB and MAPK-associated cellular stress, and modulation of Bax/Bcl-2/caspase-3 apoptotic signaling. Histopathological findings further supported preservation of neuronal architecture following Q-SLN treatment. Overall, the findings suggest that Q-SLNs can enhance the delivery and neuroprotective effectiveness of quercetin through coordinated antioxidant, anti-inflammatory, anti-apoptotic, and neuronal survival mechanisms. Further pharmacokinetic, biodistribution, long-term safety, and translational studies are required to establish their clinical potential.