Abstract
ABSTRACT: Pediatric high-grade gliomas (pHGGs) are among the most devastating cancers in children. These tumors have remained largely incurable, despite the many approaches that have been applied for their treatment. Here we use scaffolds of glycopeptide nanostructures designed for regenerative therapies to bind and present bone morphogenetic protein (BMP-4) in vivo to differentiate glioma cells and render them more susceptible to traditional chemotherapeutics. Interestingly, we discovered that the presentation of BMP-4 on these glycopeptide structures alone, without the use of a traditional chemotherapy, resulted in reduced tumor growth and enhanced survival in an orthotopic xenograft pediatric high-grade glioma tumor mouse model. Thus, this strategy has the potential to serve as a future chemotherapy-free platform for treating pHGGs which may have significantly reduced comorbidities. LAY SUMMARY: Pediatric glioblastoma (pGBM) is an aggressive brain cancer with poor survival rates despite surgery, radiation, and chemotherapy. The growth factor BMP-4 shows promise as a treatment, but its short half-life limits its potential as a future pGBM therapeutic. We developed nanostructures made from sugar-inspired molecules known as glycopeptide amphiphile molecules (gPA) that can bind, stabilize, and enhance the activity of BMP-4. When presented on gPA, BMP-4 directed pGBM cells to become less stem cell-like which slowed tumor growth in a mouse model. This approach highlights a potential strategy to improve BMP-4 delivery to advance therapeutic options for children with pGBM. FUTURE WORK: Development of chemically scalable glycosylated supramolecular structures, such as the one described here, can be used to bind and present BMP-4 as well as other proteins for future drug delivery applications in the nervous system and beyond. Future research should also investigate how these therapies can be co-administered with chemotherapeutics. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40883-025-00543-5.