Engineered nanoplatforms for brain-targeted co-delivery of phytochemicals in Alzheimer's disease: Rational design, blood-brain barrier penetration, and multi-target therapeutic synergy.

Alzheimer's disease (AD) presents significant therapeutic challenges due to its multifactorial pathology, the inefficacy of traditional single-target drugs, and the poor bioavailability and limited blood-brain barrier (BBB) penetration of promising multi-target phytochemicals like curcumin, resveratrol, and quercetin. This review systematically examines the rational design and recent advancements in engineered nanoplatforms for brain-targeted co-delivery of phytochemicals in AD. Nanotechnology leverages lipid-based systems (liposomes, solid lipid nanoparticles), polymer-based carriers (PLGA nanoparticles), inorganic nanosystems (gold, selenium nanoparticles), and biologically-derived vehicles to significantly enhance phytochemical stability, targeting efficiency, and brain accumulation. Strategic surface functionalization with BBB-translocating ligands, including transferrin receptor antibodies and RVG29 peptide, combined with stimuli-responsive mechanisms exploiting the pathological microenvironment (pH, enzyme sensitivity), enables efficient BBB penetration and lesion-specific drug release. These nanodrug delivery systems demonstrate substantial cognitive improvement in AD animal models through synergistic multi-pathway effects: inhibiting Aβ aggregation, modulating Tau phosphorylation, reducing neuroinflammation, and enhancing antioxidant activity, often at markedly reduced doses compared to free drugs. While preclinical results are compelling, critical challenges remain in nanocarrier long-term biosafety, scalable manufacturing, and clinical translation. This review provides a comprehensive framework and technical insights for developing efficient, safe, and translatable nanotherapeutics for AD.