RNAi-based spherical nucleic acid nanoconjugates for the treatment of pediatric high-grade glioma

Pediatric high-grade gliomas (p-HGGs), including Glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG) are the most aggressive primary central nervous system (CNS) tumors in children and young adults, and responsible for the majority of cancer-related mortality with a median survival of only 12-16 months. Such dismal prognosis has not changed significantly over the past decades, as effective chemotherapy regimens for p-HGG have yet to be identified. While efforts in the basic sciences have unraveled a plethora of cancer genes implicated in the genesis of p-HGG, they have, however, rarely led to the implementation of gene-specific, i.e., ‘targeted’ therapies, in part, because many cancer genes cannot be targeted by conventional pharmacological means, such as small molecules or biotherapeutic antibodies, and are classified as ‘undruggable’. In addition, brain and brain tumor tissue is separated from circulating blood by the blood-brain-barrier (BBB), which restrict the diffusion of macromolecules, including most therapeutic agents. Consequently, two of the most fundamental questions in p-HGG research and drug development are: How can therapeutic agents be effectively delivered to intracerebral tumor sites to specifically target cancer genes? And how can ‘undruggable’ cancer genes be functionally neutralized?