Here, we combined for the first time a promising nanosystem based on a nontoxic natural-derived PMLA platform with covalently attached multiple AP-2 peptides for superior BBB delivery of mRNA inhibitors against c-Myc and EGFR/EGFRvIII to treat GBM, in combination with the checkpoint inhibitor, αPD-1 mAb, to achieve maximum treatment efficacy. Here, MYC is linked to glioblastoma.