Dendrimer Conjugates for Light-activated Delivery of Antisense Oligonucleotides.

Therapeutic oligonucleotides, such as splice switching ONs (SSOs), provide opportunities for treating serious, life-threatening diseases. However, the development of ONs as therapeutic agents has progressed slowly, because difficult cytosolic delivery of SSOs into the 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 a 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 into the cytosol and accumulate in the nucleus. Furthermore, the PCI mediated cytosolic delivery of SSOs effectively enhanced their nuclear splice switching activity.