Myotonic dystrophy type 1 (DM1) is a complex autosomal dominant neuromuscular disorder that affects approximately 1 in 8,000 individuals. DM1 impacts multiple organ systems, including skeletal muscle, heart and central nervous system (CNS), leading to a diverse range of symptoms. Despite ongoing research efforts, no curative treatments are currently approved and readily available to patients. Antisense oligonucleotide (ASO) based therapies are some of the most advanced treatments being tested in DM1 patient clinical trials. These approaches utilise ASOs conjugated to moieties, such as cell-penetrating peptides or antibodies, designed to enhance their delivery into skeletal muscles and the heart. However, no therapy has yet been specifically developed that aims to additionally penetrate the CNS and treat the neurological symptoms experienced by patients. Furthermore, cell-penetrating peptide ASO conjugates (CPP-ASOs) can be associated with nephrotoxicity at higher doses, resulting in a trade-off between efficacy and toxicity, highlighting the need for further optimization to broaden their therapeutic window. In this study I have tested CPP-ASO and antibody-ASO strategies for treatment of critically affected DM1 tissues: skeletal muscle, heart and CNS. In vitro assessment of the novel CPP-ASO, DEL01-(CAG)7, identified DEL01-(CAG)7 as a leading CPP-ASO candidate, with a more favorable therapeutic window and lower toxicity compared to earlier CPP-ASO iterations. Subsequent in vivo testing confirmed these findings, demonstrating enhanced delivery to skeletal muscle, heart and significantly reduced nephrotoxicity, relative to its previous CPP-PMOs. Although, DEL01-(CAG)7, was unsuccessful in treating the milder DMSXL mouse model for DM1, it successfully reversed the DM1 phenotype in the more severe HSA-LR mouse model. Coupled with its promising safety profile these results overall support the continued development of DEL01-(CAG)7 towards clinical trials. To address the challenge of CNS delivery in DM1, I also tested the potential of ASO conjugation to a CNS optimized, anti-transferrin receptor 1 (anti-TfR1)- targeting antibody. The antibody-ASO conjugate, BBT-8D3130-(CAG)7, was evaluated in vivo and successfully increased ASO distribution to the CNS. However, although systemically delivered, it failed to also achieve sufficient concentrations for the effective of the DM1 phenotype correction in skeletal muscles. It was concluded that this was likely due to the specific chemical properties of the compound rather than inherent limitations of anti-TfR1 antibodies, suggesting that further optimization of the conjugate’s chemical characteristics is necessary to improve therapeutic efficacy. Nevertheless, the study serves as a proof-of-concept for being able to treat the CNS in DM1 using anti-TFR1 targeting delivery strategies. Overall, this study highlights promising advancements in ASO-based therapies for DM1, with DEL01-(CAG)7 showing potential for further preclinical development as a safer alternative to current CPP-PMOs and anti-TfR1 targeting offering a promising strategy for addressing CNS involvement. Furthermore, the study findings underscore the need for continued optimization of ASO conjugates to balance safety and efficacy while addressing the challenges of multi-organ targeting.