The first stage of this research proposal consists of synthesis and chemical functionalization of graphene nanosheets by 1,3-dipolar cycloaddition, to introduce positively charged amine groups, followed by introduction of alkyne groups. Water dispersibility and cell targeting will be enhanced by conjugation of hetero-bifunctional maleimide/azide-terminated polyethylene glycol to graphene by click chemistry (alkyne/azide). Transferrin receptor (TfR1)-targeting and thiol-modified aptamers, selecte d using the iterative protocol SELEX, will be subsequently conjugated to maleimide groups. The nanosystems physico-chemical characteristics will be evaluated by spectroscopic and biophysical techniques, while the membrane translocation properties will be investigated using a transwell co-culture model that mimics the phenotype of the BBB. The targeted nanocarrier that shows optimal physico-chemical properties and enhanced capacity to translocate across the BBB and bind specifically to brain tu mor cells will be further modified, by conjugation with miRNA mimics and/or chemotherapeutics, to enhance its therapeutic potential. At this stage, the anti-tumoural activity of different combinations of mimics and/or drugs will be evaluated in different cultured glioma cell lines and glioma-initiating stem-like cells. In the final stage of this proposal, the therapeutic potential of the most promising formulation will be evaluated, following systemic administration, in several orthotopic mouse models of disease.