Ardah_2026_Discov.Nano_21_

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and is characterized by amyloid-beta deposition, tau pathology, synaptic dysfunction, and progressive cognitive decline. Currently approved symptomatic therapies, including acetylcholinesterase inhibitors and the NMDA receptor antagonist memantine, provide modest and time-limited benefit and do not directly modify upstream disease drivers. This review synthesizes recent nanomedicine strategies that aim to bridge this gap by integrating biomarker-oriented nanosensors and imaging probes for earlier detection with targeted nanocarriers designed to overcome delivery barriers, particularly the blood-brain barrier, while improving pharmacokinetics and limiting off-target exposure. We highlight converging design principles, including stimulus-responsive release, receptor- and ligand-guided targeting, biomimetic coatings, and organelle-focused delivery to mitochondria and lysosome-autophagy pathways. Beyond repackaging existing agents, nano-enabled approaches are discussed in relation to amyloid and tau clearance or neutralization, redox and mitochondrial rescue, microglia-centered immunomodulation, and regenerative support for neuronal and neurovascular repair. To move beyond a descriptive overview, this review presents a stage-informed and pathology-guided framework for matching nanomedicine design to amyloid-predominant, tau-dominant, neuroinflammatory, mitochondrial, and advanced neurovascular phenotypes. We also evaluate translational constraints, including long-term safety, biodistribution, reproducibility, immunogenicity, scalable manufacturing, regulatory characterization requirements, and the trade-off between biological sophistication and clinical manufacturability. Finally, we distinguish platforms with nearer-term translational potential, such as selected lipid, polymeric, and extracellular vesicle-based systems, from exploratory multifunctional inorganic or highly complex biomimetic designs. This balanced framing clarifies where nanomedicine may realistically advance disease-modifying therapy while identifying evidence gaps that still limit translation.