A novel brain targeting MnOx-based MI-3 nanoplatform for immunogenic cell death initiated high-efficiency antitumor immunity against orthotopic glioblastoma

As the most invasive and lethal primary intracranial malignant tumor, the implementation of immunotherapy to glioblastoma (GBM) is still severely hindered by the limitations of the blood–brain barrier (BBB) and low tumor immunogenicity. Herein, a nanoplatform composed of rabies virus glycoprotein 29 (RVG29)-modified menin-mixed lineage leukemia (MLL) inhibitor (MI-3)-loaded MnOx nanoparticles (MMR NPs) is synthesized for effective GBM therapy through eliciting robust antitumor immune responses. After intravenous injection, MMR NPs can firstly cross the BBB and reach the tumor site due to the existence of RVG29. Then the immunogenic cell death (ICD) of GBM is achieved through MnOx induced reactive oxygen species (ROS) generation and ferroptosis. Meanwhile, MI-3, a specific small molecule inhibitor for MLL-rearranged acute myeloid leukemia, is innovatively applied to GBM treatment and found to further cause robust apoptosis and DNA damage. Collectively, the brain targeted MMR NPs realize high-efficiency tumor growth inhibition and ICD-initiated antitumor immunity activation. This work expands the indications of nanoimmunotherapy to intracranial malignancies and explores the feasibility of transforming "cold" tumors into "hot" tumors strategy for GBM.