Bioconjugates for improved delivery of oligonucleotide therapeutics to the central nervous system

Oligonucleotide therapeutics, including antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), have gained increasing attention as a novel modality for gene-targeted interventions for central nervous system (CNS) disorders, particularly in the context of rare and inherited neurological conditions. By correcting pathogenic abnormalities in gene splicing or expression, oligonucleotide therapeutics offer a combination of extreme specificity and disease-modifying or even curative effects. However, achieving robust delivery to the CNS after systemic administration remains a significant challenge due to the presence of the blood-brain barrier and the intrinsic physicochemical limitations of oligonucleotide therapeutics, such as their large molecular size, high charge, and susceptibility to enzymatic degradation. Peptide-, antibody-, and lipid-based conjugates have emerged as versatile strategies for CNS oligonucleotide delivery, offering distinct advantages in molecular recognition, tunability, biocompatibility, and structural uniformity. Here, we review emerging design principles for engineering peptide, antibody, and lipid conjugates to enhance binding affinity, target selectivity, pharmacokinetics, and pharmacodynamics of oligonucleotide therapeutics for CNS applications. We also discuss how engineered delivery platforms have the potential to improve therapeutic efficacy across a spectrum of neurological disorders, from rare hereditary syndromes to highly prevalent neurodegenerative diseases.