Review of nanoparticle systems for Alzheimer's disease brain delivery challenges

Alzheimer's disease (AD) is the leading cause of dementia worldwide and represents a growing public health challenge in aging societies. Despite extensive research efforts, currently approved therapies provide only limited symptomatic benefit and do not halt disease progression. A major obstacle to effective treatment is the blood–brain barrier (BBB), which severely restricts the brain delivery of most therapeutic agents. Nanoparticle-based drug delivery systems have emerged as a promising strategy to overcome BBB-related limitations by enabling precise control over physicochemical properties such as size, surface characteristics, and material composition. These properties can improve drug solubility, stability, pharmacokinetics, and targeted brain accumulation while reducing systemic toxicity. However, efficient BBB penetration and clinically feasible translation remain major challenges. This review summarizes key design principles for nanoparticles intended for AD therapy and highlights representative platforms with translational considerations, particularly lipid-based and polymer-based nanoparticles. In addition, alternative delivery strategies—including nose-to-brain nanoparticle systems and nanoparticles exploiting receptor-mediated and adsorptive-mediated transcytosis, as well as synaptic dysfunction targeting—are discussed. Collectively, this review outlines current advances and future directions for nanoparticle-mediated therapeutic delivery in AD.