Novel aptamers targeting heparan sulfate for delivery of RNA therapeutics in Alzheimer's disease.

Heparan sulfate (HS) proteoglycans are abundant, sulfation-patterned glycosaminoglycans on brain cells and the neurovascular unit that interact with amyloid-β (Aβ) and tau, aggregate and propagate proteopathic species, and modulate cellular uptake pathways. Aptamers are short, chemically synthesized single-stranded nucleic acids that fold to form high-affinity ligands. Novel aptamers bind specific HS motifs for targeting ligands to deliver RNA therapeutics (siRNA, antisense oligonucleotides, mRNA, RNA aptamer-cargo hybrids) into the brain and diseased cells in Alzheimer's disease (AD). We cover diagnostic aptamers, SELEX approaches adapted for glycans and HS, chemistry, optimization (AI/machine-learning-enabled design), novel therapeutic applications, delivery vehicles and conjugation strategies, catalytic aptamers/ribozymes, and challenges for clinical translation. We propose a workflow-in-silico HS motif mapping and machine learning (ML)-guided sequence design through microfluidic/in-vivo SELEX, site-specific chemical modification for nuclease resistance and blood-brain barrier (BBB) transcytosis, to scalable GMP manufacture. Aptamer-HS technology could enable the precision delivery of RNA therapeutics in AD.