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Objective: The purpose of this research is to formulate a biomimetic drug delivery system, which can selectively target glioblastoma (GBM) to deliver the antitumor agent, Gboxin, a novel Complex V inhibitor. Gboxin can specifically inhibit GBM cell growth but not normal cells. Methods: In the present study, we utilized red blood cell (RBC) membrane and U251 cell membrane to obtain a hybrid biomimetic membrane (RBC-U), and prepared RBC-U coated Gboxin-loaded mesoporous silica nanoparticles ((MSNs/Gboxin)@[RBC-U]) for GBM chemotherapy. The zeta potential, particle size, and morphology of (MSNs/Gboxin)@[RBC-U] were characterized. The cellular uptake, effect of cells growth inhibition, biocompatibility, and specific self-recognition of nanoparticles were evaluated. Results: The (MSNs/Gboxin)@[RBC-U] was successfully fabricated and possessed high stability in the circulation system. The drug loading of Gboxin was 13.9%. (MSNs/Gboxin)@ [RBC-U] could effectively retain drugs in the physiological environment and released Gboxin rapidly in the tumor cells. Compared to the MSNs/Gboxin, the (MSNs/Gboxin)@[RBC-U] exhibit highly specific self-recognition to the source cell line. Additionally, the (MSNs/Gboxin) @[RBC-U] showed excellent anti-proliferation efficiency (IC50 = 0.21 μg/mL) in the tumor cell model and few side effects in normal cels in vitro. Conclusion: The (MSNs/Gboxin)@[RBC-U] exhibited significant anti-cancer effects in vitro and the specific self-recognition to GBM cells. Hence, (MSNs/Gboxin)@[RBC-U] could be a promising delivery system for GBM targeted therapy.