Shah_2026_Mol.Neurobiol_63_

Alzheimer's disease (AD) is the most prevalent cause of dementia, affecting over 50 million individuals worldwide, with projections suggesting a tripling of cases by 2050. Current Food and Drug Administration (FDA)-approved treatments, including cholinesterase inhibitors, N-Methyl-D-aspartic acid (NMDA) receptor antagonists, and monoclonal antibodies, provide only modest symptomatic relief or partial disease modification. Their limitations include poor blood-brain barrier penetration, systemic side effects, and reduced efficacy in advanced stages. This has caused the exploration of novel nanotechnology-based interventions. This review synthesizes recent evidence from preclinical and translational studies on SeNPs for AD therapy. Also covering their synthesis methods (physical, chemical, and biological), surface engineering approaches, drug loading strategies, and mechanisms of action were systematically examined. SeNPs exhibit dual functionality as therapeutic agents and drug carriers. Functionalized SeNPs have shown the ability to cross the BBB, but this efficiency depends on particle size (typically < 100 nm) and surface ligands such as transferrin, rabies virus glycoprotein 29-peptide (RVG29), or transferrin-guiding peptide (TGN). Studies using ligand-modified SeNPs demonstrate improved BBB transport and enhanced modulation of oxidative stress, amyloid-beta (Abeta) aggregation, and neuroinflammation. SeNPs exhibit neuroprotective activity in several preclinical models, primarily attributed to antioxidant and anti-inflammatory mechanisms. Although encouraging preclinical data support their promise, systematic toxicological assessment and optimization of stability are required. With advances in green synthesis, surface engineering, and theranostic applications, SeNPs may represent a new Framework in precision nanomedicine for Alzheimer's disease.