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• Glioblastoma is the most aggressive primary central nervous system cancer. • Peptide stapling technique via introduction of an all-hydrocarbon macrocyclic bridge. • A novel ligand of LRP1 which is widely expressed in glioma, BBB, BBTB, tumor angiogenesis and vascular mimicry. • Stapled RAP12 peptide as a multifunctional glioma-targeted ligand. • LRP1-mediated polymeric micelles to deliver chemotherapeutics. The RAP12 peptide derived from miniaturization of receptor-associated protein (RAP) holds binding affinity with low-density lipoprotein receptor-related protein-1 (LRP1). However, RAP12 exhibited weak α -helical segments when taken out of the stabilizing protein context. Considering that the α -helix is a common structural motif of the peptide to mediate ligand-receptor interactions, we utilized the peptide stapling technique to generate RAP12 with all-hydrocarbon tethers, named stapled RAP12 (ST-RAP12). This optimized ST-RAP12 was verified to obtain an increased α -helical content, binding affinity with LRP1 and serum stability compared to RAP12. In addition, ST-RAP12 exhibited enhanced cellular internalization of bEnd.3 cell, U87 glioma cells and HUVEC. Furthermore, the ability of ST-RAP12 to overcome in vitro BBB/BBTB was also potentiated. Next, ST-RAP12 peptide was further applied to modify polymeric materials to construct ST-RAP12-micelles. It is verified that the ST-RAP12-micelles effectively penetrated BBB/BBTB and targeted glioma in vitro/vivo , and immunofluorescence studies demonstrated its targeting ability to tumor angiogenesis and LRP1. Moreover, ST-RAP12-micelles efficiently delivered paclitaxel (PTX) to glioma, prolonged the survival time of glioma-bearing mice, inhibited tumor angiogenesis and induced glioma apoptosis, which displayed obvious anti-glioma efficacy. Overall, ST-RAP12 is anticipated to be a widely used LRP1-targeted peptide and could be translated as a multifunctional ligand for glioma-targeted drug delivery. [ABSTRACT FROM AUTHOR]