Dendrimer Conjugates for Light-activated Delivery of Antisense Oligonucleotides

Therapeutic oligonucleotides, such as splice switching ONs (SSOs), provide opportunity for treating serious, life-threatening diseases. However, the development of ONs as therapeutic agents has progressed slowly, because difficult cytosolic delivery of SSOs into cytosol and nucleus remains a major barrier. Photochemical internalization (PCI), a promising strategy for endosomal escape, was introduced to disrupt the endosomal membrane using light and photosensitizer. Here we constructed Poly(amido amine) (PAMAM) dendrimer conjugates to simultaneously deliver SSOs and photosensitizers into endo/lysosomal compartments. After photo-irradiation, considerable ONs were observed to diffuse to cytosol and accumulate in nucleus. Furthermore, the PCI mediated cytosolic delivery of SSOs effectively enhanced their nuclear splice switching activity.