Rational design of a glycopeptide probe system based on a reconfigurable immune microenvironment

Glioma is a highly challenging human malignancy and conventional drugs typically exhibit low blood-brain barrier (BBB) permeability as well as poor tumor targeting. To complicate matters further, recent advances in research on oncology have highlighted the dynamic and complex cellular networks within the immunosuppressive tumor microenvironment (TME) that complicate glioma treatment. Therefore, precise and efficient targeting of tumor tissue, whilst reversing immunosuppression, may provide an ideal strategy for the treatment of gliomas. Here, by using the “one-bead-one-component” combinatorial chemistry approach, we designed and screened a peptide that can specifically target brain glioma stem cells (GSCs), which was further engineered into glycopeptide-functionalized multifunctional micelles. We demonstrated that the micelles can carry DOX and effectively penetrate the BBB to achieve targeted killing of glioma cells. Meanwhile, mannose confers a unique tumor immune microenvironment modulating function to the micelles, which can activate the anti-tumor immune response function of tumor-associated macrophages and is expected to be further applied in vivo. This study highlights that glycosylation modification of targeted peptides specific to cancer stem cells (CSCs) may serve as an effective tool to improve the therapeutic outcome of brain tumor patients.