Diffuse Midline Glioma (DMG) is an inoperable pediatric brain tumor with no good treatment options. Our group has developed a novel treatment modality for this disease and others, using mRNA vaccines consisting of tumor derived antigens packed into a unique lipid nanoparticle (NP). They can provide near immediate immune induction against inciting malignancies. RNA-NPs can thus be harnessed as an effective therapy for patients with DIPG and other refractory malignancies. In addition, DIPG has a highly conserved H3K27M mutation that serves as an excellent target for these therapies. Based on the above, we propose exploring the immunogenicity of RNA-NPs targeting the DIPG H3K27M mutation, as well as the feasibility, safety, and anti-tumor activity of tumor loaded RNA-NP vaccines in animal models. These RNA NPs have shown survival benefit in our preclinical murine model of DMG. Among these animals with significant survival benefit, there is development of hydrocephalus, which is thought to be secondary to increased lesion size secondary to an immunotherapeutic response during treatment. In our clinical trials investigating RNA NPs as a treatment for canine glioma in adult dogs, we saw a similar effect in MRI imaging of animals that became long-term survivors. Following detailed analysis of these lesions in mouse, canine and human patients during RNA-NP therapy, there appears to be features of both reactive gliosis and traditional pseudoprogression (immune infiltration), suggesting a new radiographic diagnosis I have named paraprogression. I hypothesize that paraprogression is a novel radiographic entity characterized by reactive gliosis and increased lesion size in therapeutic responders. In this study, I aim to visualize paraprogression using advanced MRI techniques, elucidate the mechanism behind the increase in lesion size, and combat this effect without compromising our promising survival benefit conferred by RNA NP vaccine in our preclinical DMG model.