Glioblastoma multiforme (GBM) is an aggressive primary brain tumor， for which there is no cure. Treatment effectiveness for GBM has been limited due to tumor heterogeneity， an immunosuppressive tumor microenvironment (TME)， and the presence of the blood-brain barrier， which hampers the transport of chemotherapeutic compounds to the central nervous system (CNS). High-density lipoprotein (HDL)-mimicking nanodiscs hold considerable promise to achieve delivery of bioactive compounds into tumors. Herein， we tested the ability of synthetic HDL nanodiscs to deliver chemotherapeutic agents to the GBM microenvironment and elicit tumor regression. To this end， we developed chemo-immunotherapy delivery vehicles based on sHDL nanodiscs loaded with CpG， a Toll-like receptor 9 (TLR9) agonist， together with docetaxel (DTX)， a chemotherapeutic agent， for targeting GBM. Our data show that delivery of DTX-sHDL-CpG nanodiscs into the tumor mass elicited tumor regression and antitumor CD8 T cell responses in the brain TME. We did not observe any overt off-target side effects. Furthermore， the combination of DTX-sHDL-CpG treatment with radiation (IR)， which is the standard of care for GBM， resulted in tumor regression and long-term survival in 80% of GBM-bearing animals. Mice remained tumor-free upon tumor cell rechallenge in the contralateral hemisphere， indicating the development of anti-GBM immunological memory. Collectively， these data indicate that sHDL nanodiscs constitute an effective drug delivery platform for the treatment of GBM， resulting in tumor regression， long-term survival， and immunological memory when used in combination with IR. The proposed delivery platform has significant potential for clinical translation.