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Antibody‐oligonucleotide conjugate (AOC) affords preferential cell targeting and enhanced cellular uptake of antisense oligonucleotide (ASO). Here, we have developed a modular AOC (MAOC) approach based on accurate self‐assembly of separately prepared antibody and ASO modules. Homogeneous multimeric AOC with defined ASO‐to‐antibody ratio were generated by L‐DNA scaffold mediated precise self‐assembly of antibodies and ASOs. The MAOC approach has been implemented to deliver exon skipping ASOs via transferrin receptor (TfR1) mediated internalization. We discovered an anti‐TfR1 sdAb that can greatly enhance nuclear delivery of ASOs. Cryo‐EM structure of the sdAb‐TfR1 complex showed a new epitope that does not overlap with the binding sites of endogenous TfR1 ligands. In vivo functional analyses of MAOCs with one ASO for single exon skipping and two ASOs for double exon skipping showed that both ASO concentration and exon skipping efficacy of MAOC in cardiac and skeletal muscles are dramatically higher than conventional ASOs in the transgenic Duchenne muscular dystrophy (DMD) mouse model. MAOC treatment was well tolerated in vivo and not associated with any toxicity‐related morbidity or mortality. Collectively, our data suggest that the self‐assembled MAOC is a viable option for broadening the therapeutic application of ASO via multi‐specific targeting and delivery.
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