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Current standard of care for many CNS tumors involves surgical resection followed by chemotherapy and/or radiation. Some pediatric brain tumor types are infiltrative and diffuse in nature, which reduces the role for surgery. Furthermore, children are extremely vulnerable to neurological sequelae from surgery and radiation therapy, thus alternative approaches are in critical need. As molecular targets underlying various cancers become more clearly defined, there is an increasing push for targeted gene therapies. Viral vectors and nonviral nanoparticles have been thoroughly investigated for gene delivery and show promise as vectors for gene therapy for pediatric brain cancer. Here, we review inorganic and organic materials in development for nanoparticle gene delivery to the brain with a particular focus on safety.