Antisense oligonucleotide (ASO) modulates gene expression with high selectivity and specificity, offering a promising therapy for central nervous system (CNS) disorders. However, the poor permeability of ASO across the blood-brain barrier (BBB) limits its therapeutic success. Here, we designed and synthesised several BBB-permeable ASOs by incorporating a cell penetrating peptide, Apolipoprotein E (ApoE) and an endosomal escape domain, hemagglutinin (HA2) to enhance the expression of survival motor neurone 2 (SMN2) in Spinal Muscular Atrophy (SMA). Our results showed that all peptide-ASO conjugates increase the expression of full-length functional mRNA of the SMN2 gene in SMA patient-derived fibroblast, indicating the effectiveness of the ApoE cell penetrating peptide and HA2 endosomal escape domain in delivering the ASO across the fibroblast membrane. Specifically, the retro-inverso peptide RI-HA2-ApoE (133-150) yielded a 2.3-fold increase in the expression of the full-length SMN2 gene at 1 uM with minimal toxicity at 2 uM. Moreover, it was found to possess an extended half-life (t1/2 = 1.6 h), indicating the stability against protease degradation in human serum. This delivery platform based on BBB-penetrating peptides enhances the CNS bioavailability of ASO targeting SMN2, paving the way for the development of systemically administrated neurotherapeutics for CNS disorders.