Antisense oligonucleotides (ASOs) are emerging therapeutics for various diseases, with more than 12 ASOs currently approved by the FDA. Amongst them, only two are for brain-related diseases, amyotrophic lateral sclerosis and spinal muscular atrophy (SMA). The slow progress in translation of ASOs targeting neurological diseases is not due to the lack of ASO potency but rather their inability to reach their CNS target due to the presence of a formidable blood-brain barrier (BBB) that impedes the CNS entry of most neurotherapeutics. Therefore, to address this limitation, we have developed a safe and highly efficient CNS drug delivery platform based on BBB-penetrating peptides (BPP). We have demonstrated the ability of the BPPs to systemically (i.v. route) deliver an FDA-approved ASO (Spinraza) into the CNS and significantly upregulate the level of target gene (SMN2) in the brain (20%) and spinal cord (55%) in SMN2 transgenic adult mice. We have also assessed the brain distribution of Cy7-labelled BPP-ASO conjugate. We have shown that 78% of i.v. injected Cy7-BPP-ASO conjugate crossed the BBB and are in the brain parenchyma, with 11% localized within neuronal cells. Together, these findings establish this BPP platform as one of the most effective and advanced peptide-based CNS delivery technologies developed to date for systemic delivery of large biomolecules such as ASOs.