Alzheimer's disease (AD), the most common cause of dementia, is driven by intersecting proteopathic and inflammatory processes, including amyloid-β aggregation, tau pathology, neuroinflammation, synaptic dysfunction, and progressive neuronal loss. Current therapies remain insufficient to address its multifactorial nature. RNA-based therapeutics, including antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs), enable precise modulation of disease-relevant pathways. However, their clinical translation in AD is constrained by poor stability, immunogenicity, and limited delivery across the blood-brain barrier (BBB). Nanotechnology has enabled clinically successful RNA delivery in several non-CNS indications, yet nanoparticle (NP)-mediated nucleic acid delivery has not been evaluated in AD clinical trials to date. In this review, we integrate the emerging clinical landscape of CNS-directed RNA therapeutics with the preclinical evidence supporting NP-enabled delivery to AD-relevant targets and cell types, and we highlight design features that enhance stability, BBB transport, endosomal escape, and cellular selectivity. We further delineate the key translational requirements to advance these platforms from proof-of-concept to first-in-human studies, including scalable, reproducible manufacturing; rigorous safety and tolerability assessments; mitigation of innate immune activation; and consistent, quantifiable brain exposure and target engagement. Finally, we discuss next-generation strategies, such as multifunctional, stimulus-responsive nanocarriers and combinatorial RNA payloads, aimed at addressing AD heterogeneity and enabling durable, mechanism-based disease modification.
