Therapeutic Oligonucleotides for Neurodegenerative Diseases: Aptamer Strategies and Clay Nanoparticle‐Based Delivery

Aptamers have emerged as promising therapeutic oligonucleotides (TOs) due to their structural adaptability, high binding affinity, and remarkable specificity toward diverse biological targets. Among them, G-quadruplex-forming aptamers stand out for their unique secondary structures and distinct chemical properties. Their potential in neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's lies in their ability to inhibit protein aggregation and modulate pathogenic pathways. However, their application is hindered by enzymatic degradation and limited membrane permeability. To overcome these issues, chemical modifications, such as backbone and sugar alterations, and nanomaterial-based delivery strategies have been developed. Notably, clay nanoparticles, such as halloysite nanotubes and montmorillonite, have gained attention as effective carriers for TOs, enhancing their structural stability and bioavailability. This review discusses recent advancements in aptamer-based TOs, with a focus on G-quadruplex-forming oligonucleotides, their therapeutic potential in neurodegenerative diseases, and innovative nanocarrier systems that can improve their stability and targeted delivery. Finally, it highlights current challenges and future directions in the chemical design and formulation of aptamer-based therapeutics for targeted applications.