Antisense oligonucleotides (ASOs) are emerging therapeutics for various diseases, with more than 10 ASOs currently approved by the FDA. Amongst them, only one is for CNS related disease, spinal muscular atrophy (SMA). The slow progress in translation of ASOs targeting neurological diseases is not due to the lack of ASOs 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 21% of i.v. injected Cy7-BPP-ASO conjuagte are trapped in the brain capillaries and 79% have crossed the BBB and are in the brain parenchyma. This work provides a proof-of-principle that BBB-penetrating peptides are a non-invasive CNS delivery platform capable of efficient delivery of ASOs into the CNS to achieve the desired therapeutic effect.