Brain-targeted delivery of siRNA via non-viral delivery systems, the therapeutic strategy for Alzheimer's disease—Unveiling challenges and prospects

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive and behavioral issues, posing significant public health challenges. Small interfering RNAs (siRNAs) offer the potential to selectively silence AD-related pathogenic genes. This review first outlines the diverse pathogenic mechanisms and hallmark pathologies of AD, then spotlights the key genes now being silenced by siRNA for therapeutic intervention. These genes encompass those directly implicated in amyloidogenesis, tau phosphorylation, and neuroinflammation, along with those aberrantly up-regulated and associated with AD pathology. Finally, it summarizes recent research on non-viral and local siRNA delivery strategies including lipid, polymer, quantum dots, inorganic materials, extracellular vesicles, and conjugates aimed at effectively penetrating the blood-brain barrier while overcoming intra- and extracellular barriers to target key AD pathways. These findings underscore the promise of siRNA therapy in addressing AD pathology and provide valuable insights into overcoming delivery challenges.