High grade gliomas (HGG) are a group of CNS tumors refractory to currently existing therapies, which routinely leads to early recurrence and a dismal prognosis. Recent advancements in nucleic acid-based therapy using a wide variety of different molecular targets and non-viral nanocarrier systems suggest that this approach holds significant potential to meet the urgent demand for improved therapeutic options for the treatment of these tumors. This review provides a comprehensive and up-to-date overview on the current landscape and progress of preclinical and clinical developments in this rapidly evolving and exciting field of research, including optimized nanocarrier delivery systems, promising therapeutic targets and tailor-made therapeutic strategies for individualized HGG patient treatment.