Preventing smoking initiation among vulnerable adolescents: a process evaluation of the KickAsh!-intervention in Flemish youth social work settings.

Alzheimer’s disease (AD), the leading cause of neurodegeneration worldwide, manifests as progressive memory loss, cognitive decline, and synaptic dysfunction, posing a major threat to the quality of life in the aging population worldwide [–]. Despite extensive research, the pathogenesis of AD is multifactorial, with mounting evidence implicating chronic neuroinflammation and glutamate-induced excitotoxicity as two critical and interrelated drivers of disease progression [–]. Neuroinflammation, primarily mediated by persistently activated microglia and elevated oxidative stress, disrupts neuronal homeostasis and exacerbates synaptic damage [, ]. Concurrently, excessive glutamate stimulation triggers calcium overload and excitotoxic neuronal death via overactivation of N-methyl-D-aspartate (NMDA) receptors [, ]. Chemically synthesized small-molecule drugs such as memantine, a clinically approved NMDA receptor antagonist, have demonstrated partial efficacy in mitigating excitotoxicity [–]. However, their therapeutic performance is often limited by insufficient enrichment, rapid systemic clearance, and a narrow therapeutic window associated with dose-dependent neurotoxicity [–]. These limitations highlight the urgent need for safe, effective, and noninvasive strategies that can simultaneously modulate neuroinflammatory and excitotoxic cascades in AD. Natural products have attracted considerable attention for the treatment of neurodegenerative diseases owing to their pleiotropic pharmacological activities, excellent biocompatibility, and structural diversity [–]. Tea () has been consumed as a beverage worldwide for centuries and is widely recognized for its favorable safety profile []. Tea-derived products, particularly polyphenol-rich extracts, have exhibited neuroprotective activity in AD models by modulating key pathological features such as amyloid- aggregation, microglial-mediated inflammation, and oxidative stress [–]. In addition to their pharmacological effects, tea-derived natural products often contain π-conjugated structures, including catechins and flavonoids. These features result in weak to moderate intrinsic fluorescence under UV or visible excitation, allowing label-free imaging in biological environments [, ]. However, the clinical translation of tea-derived interventions is hindered by limited aqueous solubility, intrinsically low oral bioavailability, and insufficient enrichment at neuroinflammatory loci due to restricted blood–brain barrier transport [, ].Translating tea-derived products into natural nanodrugs for high-efficacy AD treatment is therefore highly attractive, yet remains underexplored to date. In this study, we developed a multifunctional tea-derived natural nanodrug (Tea-ND) that integrates real-time fluorescence tracking with noninvasive therapy against AD pathology. This natural-origin drug was prepared by combining ancient-tree tea extracts with memantine, followed by biomimetic coating with platelet-derived extracellular vesicles for intranasal nebulized delivery. Tea-ND exhibits intrinsic fluorescence for label-free, real-time tracking at cellular and tissue levels, with preferential colocalization in activated microglia and selective accumulation within neuroinflammatory brain regions. Notably, Tea-ND demonstrates improved tolerability and reduced hippocampal damage compared with free memantine at equivalent doses in healthy mice. Moreover, this noninvasive strategy achieves efficient brain targeting and markedly improves hippocampal pathology and cognitive performance in AD mouse models. Mechanistically, the polyphenol-based antioxidant properties mitigate memantine-induced neurotoxicity, suppress oxidative stress and microglial activation, thereby alleviating neuroinflammation, restoring synaptic integrity and reducing glutamate-associated calcium overload. Our findings provide a proof of concept for developing natural nanodrugs for noninvasive and precise treatment for AD and other brain disorders.