Nanostructured Metal Complexes for Targeted Delivery in Alzheimer’s Therapy

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β
(Aβ) aggregation, tau hyperphosphorylation, metal-ion dyshomeostasis, oxidative stress, and
chronic neuroinflammation, all of which contribute to cognitive decline and neuronal loss.
Increasing evidence highlights the critical role of aberrant transition metals, such as copper, iron,
zinc, and aluminum, in accelerating protein misfolding and redox imbalance, thereby amplifying
disease pathology. Conventional therapies have shown limited efficacy due to poor blood–brain
barrier (BBB) penetration, lack of specificity, and inability to target multiple pathogenic pathways
simultaneously. Emerging nanostructured metal complexes offer a novel multimodal approach that
combines tunable physicochemical properties, versatile ligand functionalization, and incorporation
into advanced nanoformulations (e.g., liposomes, dendrimers, and polymeric nanoparticles). These
systems enhance BBB permeability, enable targeted delivery, provide controlled drug release, and
reduce systemic toxicity. Mechanistically, they inhibit Aβ aggregation, modulate tau
hyperphosphorylation, chelate excess metal ions, and provide antioxidant and anti-inflammatory
neuroprotective effects. Copper-, iron-, zinc-, ruthenium-, and platinum-based complexes have
demonstrated promising preclinical efficacy, particularly when integrated into ligand-decorated,
stimuli-responsive, or multifunctional theranostic platforms. Synergistic co-delivery with small
molecules or genetic materials further expands the therapeutic versatility. The remaining
challenges are BBB navigation, precision targeting, scalable manufacturing, and regulatory
approval. Leveraging precision medicine, artificial intelligence, and computational modeling can
accelerate rational design, optimization, and clinical translation. Overall, nanostructured metal
complexes represent a cutting-edge, multitargeted, and clinically translatable strategy for AD
therapy.