Antibody-oligonucleotide conjugates: an emerging modality for precision RNA therapeutics

RNA-targeting therapeutics have enormous potential to precisely target disease-causing RNAs, extending beyond the traditional limits of "druggability" for small molecules, antibodies, and protein-targeting cell therapies. However, one crucial limitation is that RNA-targeting drug modalities (such as oligonucleotides) cannot effectively reach diseased tissue or cell types. Antibody-oligonucleotide conjugates (AOCs) emerge as a promising frontier in aiding RNA therapeutics by harnessing antibodies to deliver drug modalities to target specific RNAs in desired tissues or cells. In this Review, we summarize the critical components of AOCs, key considerations for their design and manufacturing, ongoing AOCs in preclinical/clinical development, and disease indications. We discuss the current hurdles to improving AOC efficacy and extending its application, concluding with an outlook on the unique opportunities offered by AOCs beyond traditional oligonucleotides and small-molecule antibody-drug conjugates. We propose that, with focused efforts to overcome key challenges, AOCs have the potential to transform RNA therapeutics, offering treatment options for many previously untreatable diseases.