Abstract Background DMGs are a highly aggressive subtype of glioma that affects children and young adults. These tumors involve critical regions of the central nervous system (CNS) making surgical resection difficult. Current standard-of-care treatments offer limited benefits, and the prognosis remains dismal with a median survival of 12 months. To address this unmet need, we have developed a novel RNA-nanoparticle (RNA-NP) vaccine that encapsulates total tumor mRNA, stimulating systemic immune activation via innate and adaptive immune pathways (Sayour IND#19308). While we have demonstrated efficacy in experimental preclinical and large animal models of spontaneous glioma, we believe the therapeutic response could be improved by enhancing focal tumor delivery. Low-frequency focused ultrasound (Lo-FU) has emerged as a promising non-invasive method for achieving temporary and localized BBB disruption. This approach could enhance the delivery of RNA-NPs directly to DMG tumors, thereby optimizing immune activation and improving therapeutic outcomes. Hypothesis Combining Lo-FU with intravenous microbubble administration to disrupt the BBB will enhance RNA-NP delivery to DMG. Methods To assess CNS delivery, fluorescently labeled RNA-NPs of various sizes were tracked via intravital and ex vivo imaging in murine glioma models following Lo-FU. Durable mRNA expression was measured using intravital imaging, and whole-brain immunofluorescence was employed to quantify cellular uptake and RNA-NP transduction. Results Lo-FU enhanced CNS uptake and retention of fluorescently labeled RNA-NPs, demonstrated by increased CNS fluorescence signal at all nanoparticle sizes tested. Improved CNS transduction by RNA-LPs following Lo-FU was confirmed by elevated luciferase and TdTomato reporter expression. Conclusions Lo-FU is an effective, non-invasive strategy for improving CNS delivery of RNA-NPs, addressing the critical challenge posed by the BBB. This approach significantly enhances CNS delivery of therapeutic nanoparticles, presenting a promising adjunct to RNA-NP vaccination strategies for DMG treatment. Future studies will explore the combined approach’s impact on immune activation and long-term survival.
Moor et al. (Fri,) studied this question.