Nanoparticles that target nonamyloid and nontau pathways in Alzheimer’s disease

Alzheimer’s disease (AD) is a complex neurodegenerative disorder whose progression involves multiple pathways beyond the canonical amyloid and tau cascades. Neuroinflammation, mitochondrial dysfunction, and lysosomal impairment represent key nonamyloid and nontau pathways; preclinical evidence suggests that targeting these pathways may aid in the development of more effective treatments, although clinical validation remains pending. Owing to their ability to cross the blood‒brain barrier and their potential for precise targeting, nanostructured materials represent promising tools for modulating these pathways in preclinical models. Lipid, chitosan, and gold nanoparticles, when employed as carriers of anti-inflammatory and antioxidant compounds such as curcumin and resveratrol, have been shown in animal studies to reduce neuroinflammation and improve mitochondrial function. NPs functionalized with ligands such as triphenylphosphonium specifically target mitochondria, reducing oxidative stress and increasing ATP production by increasing drug bioavailability. Polymeric and carbon nanostructures improve lysosomal function and restore cellular homeostasis. These technologies slow disease progression by reducing neuroinflammation, improving mitochondrial dynamics, and enhancing autophagy processes. This article provides a strictly narrative review of recent advances in the use of nanostructured materials for targeting nonamyloid and nontau pathways in AD and to examine the therapeutic potential of this technology in the development of effective strategies to combat this disease. Nanoparticles enable targeted modulation of key nonamyloid and nontau pathological pathways in Alzheimer’s disease, including neuroinflammation, mitochondrial dysfunction, lysosomal impairment, ER stress, synaptic loss, and gut–brain axis dysregulation. Functionalized nanoparticles enhance blood–brain barrier penetration and subcellular delivery, significantly improving the therapeutic efficacy of antioxidants such as curcumin and resveratrol at reduced doses. Mitochondria- and lysosome-targeted nanotherapies restore bioenergetics, reduce oxidative stress, and promote autophagic clearance, addressing early cellular dysfunctions that precede amyloid and tau pathology. Emerging nanoplatforms integrate multiple functional capabilities, such as epigenetic regulation, microbiome modulation, and metabolic reprogramming, offering a holistic, systems-level approach to combat the multifactorial nature of Alzheimer’s disease.