Aptamer-based technologies for theranostics of central nervous system disorders

Abstract Aptamers are short single-stranded DNA or RNA ligands that fold into defined three-dimensional structures and bind targets with antibody-like affinity and specificity, yet retain key advantages for central nervous system (CNS) applications including chemical synthesis, low immunogenicity, thermal stability, and facile modular engineering. This review summarizes recent advances positioning aptamers as “theranostic” platforms for CNS disorders, spanning discovery, optimization, delivery, and integrated sensing. We highlight the evolution of selection technologies from classical protein-‘Systematic Evolution of Ligands by Exponential Enrichment’ (SELEX) to Cell-SELEX and in vivo SELEX, now increasingly coupled with high-throughput sequencing, bioinformatics, molecular docking/molecular dynamics, and emerging artificial intelligence/machine learning (AI/ML) approaches that learn sequence–structure–function relationships and accelerate candidate prioritization and de novo design. We discuss chemical strategies that address nuclease degradation and rapid renal clearance, while noting trade-offs between stability and folding-dependent affinity. Since blood–brain barrier (BBB) transport remains the dominant translational barrier, we evaluate non-invasive intranasal delivery, receptor-mediated transcytosis via endothelial shuttles, intrathecal administration, and vector-enabled intracellular expression for sustained neuroimmune modulation. Finally, we discuss multifunctional conjugates and carriers and CNS-focused aptamer-based sensors for neurotransmitters and misfolded proteins, alongside multiplexed aptamer proteomics for biomarker discovery and monitoring. Collectively, converging advances in selection, computation, chemistry, and delivery are enabling aptamer-based closed-loop theranostics tailored to CNS disease biology.