Research progress and development strategies of antibody-oligonucleotide conjugates

Antibody-oligonucleotide conjugates (AOCs) effectively integrate the delivery capability of antibodies with the specific gene regulatory function of oligonucleotides, offering a novel strategy for extrahepatic delivery. Unlike antibody-drug conjugates (ADCs), AOCs employ nucleic acid payloads, enabling specific gene modulation with reduced off-target effects, thus providing new avenues for treating genetic disorders. While AOC candidates for conditions such as Duchenne muscular dystrophy (DMD) have progressed to Phase III trials, their development remains constrained by limited targets like TfR1, and their activity is highly dependent on antibody selection, linker design, and modification strategies. This study delves into the fundamental principles of target selection and antibody engineering, emphasizing that the endocytic efficiency of the target receptor is a critical factor for the successful delivery of AOC therapeutics. Taking TfR1 as an example, it analyzes the advantages and disadvantages of different antibody formats, examines the structure-activity relationships between linker chemistry and pharmacokinetics/pharmacodynamics, and further explores nucleic acid modification strategies aimed at enhancing delivery efficiency. Finally, the study outlines future directions for AOC development, including advances in bispecific antibodies, peptide conjugation, gene editing, and artificial intelligence-driven approaches, aiming to provide forward-looking perspectives and a theoretical foundation for the design of AOC therapeutics.