Antibody-oligonucleotide conjugates: design principles, intracellular delivery, and translational opportunities

Abstract

Antibody-oligonucleotide conjugates (AOCs) have emerged as a promising therapeutic platform that integrates the targeting capability of antibodies with the gene-regulatory potential of oligonucleotide payloads. By enabling cell or tissue selective delivery, AOCs may extend oligonucleotide therapeutics beyond liver predominant distribution and broaden intervention strategies for intracellular targets that have historically been difficult to drug. However, their therapeutic performance is not determined by target binding alone, but also by productive intracellular delivery, including receptor mediated uptake, endosomal trafficking, payload release, and functional access to cytoplasmic or nuclear compartments. In this review, we summarize the key design principles governing AOCs performance, including target biology, antibody formats, oligonucleotide payload classes, chemical modifications, linker design, conjugation strategies, and critical quality attributes. We further discuss the intracellular fate of AOCs and highlight endosomal escape as a major rate limiting step that often constrains biological activity despite efficient cellular uptake. In addition, we review current translational progress, with particular emphasis on neuromuscular disorders, as well as emerging applications in oncology, central nervous system diseases, and other indications. Finally, we outline major challenges and future directions that are likely to shape the next generation of AOCs therapeutics.