Quercetin-Based Nanotherapeutics for Targeted Drug Delivery in Alzheimer's Disease: Comparative Insights into Molecular Mechanisms, Blood-Brain Barrier Targeting and Therapeutic Perspectives.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder driven by interconnected pathological processes, including amyloid-β (Aβ) accumulation, tau hyperphosphorylation, oxidative stress, mitochondrial dysfunction, cholinergic impairment, and chronic neuroinflammation. Quercetin, a naturally occurring flavonoid, exhibits pleiotropic neuroprotective activities by modulating oxidative stress, inflammatory signaling, pathological protein aggregation, mitochondrial function, and cholinergic pathways. However, poor aqueous solubility, rapid metabolism, limited systemic bioavailability, and restricted brain exposure constrain its therapeutic translation. Nanotechnology-based drug delivery approaches have therefore been explored to improve quercetin's physicochemical and pharmacokinetic properties and facilitate brain delivery. This review critically evaluates recent advances in quercetin-loaded polymeric nanoparticles, lipid-based nanocarriers, liposomes, inorganic systems, and biomimetic nanocarriers for AD. Particular emphasis is placed on the association between nanocarrier composition and drug-loading capacity, release behavior, stability, route of administration, and brain delivery. The review discusses BBB-targeting approaches, including receptor-mediated and adsorptive-mediated transport, alongside targeted drug-delivery strategies and the underlying molecular pathways, with particular attention to the distinction between evidence for BBB transport and actual brain exposure. The review further compares therapeutic outcomes across cellular, transgenic AD models, biodistribution, translational barriers, and regulatory considerations. Collectively, this review provides a mechanistic and comparative perspective on the potential and limitations of nanotechnology-enabled quercetin delivery and identifies priorities for developing clinically translatable nanotherapeutic strategies for AD.